Itraconazole: An Antifungal Drug With Anti Cancer Properties

Background:

Itraconazole is a FDA approved drug, developed as an orally administrated antifungal drug, and has been used clinically for many decades with a well-established safety record. It has been used in the prevention and treatment of a broad range of fungal infections, such as aspergillosis, blastomycosis, candidiasis, histoplasmosis, but also in various dermatological and nail infections.

Since relatively recently, Itraonazole has been identified as a drug with high potential to fight cancer. As it will be discussed below, some of the main mechanism related to this anti tumor action are inhibition of angiogenesis but also the inhibition of Hedgehog pathway. Both mechanism are related to most types of tumors and as a result Itraconazole may be relevant for most types of cancers.

The angiogenesis is relevant for most tumors as without blood vessels, a tumor cannot grow larger than about 1–2 mm in diameter. This seems to be the largest size at which nutrients can permeate by diffusion alone (Ref.). In order to grow further, tumors have to also grow continuously and fast blood vessels, a process which is called angiogenesis.

fungusThe inner lining of all blood vessels consists out of endothelial cells and these cells represents an essential part of new as well as preexisting blood vessels. The proliferation, migration, and differentiation of endothelial cells are integral parts of angiogenesis. In 2007, following a screen of a clinical drug library an unexpected hit indicated Itraconazole as an inhibitor of endothelial cell proliferation and thus acting as an angiogenesis inhibitor.

In this screen itraconazole was unique among other drugs tested in its ability to selectively inhibit the proliferation of endothelial cells with high potency. In sharp contrast to itraconazole, the structurally related terconazole and ketoconazole were 27- and 40-fold less potent (Ref.) Fortunately, the IC50 value of itraconazole used in these experiments was well below the steady state levels achieved with a standard oral 200 mg dose. (Ref.) This means that it is enough to use normal doses of the drug in order to reach the anticancer effects.

The upregulation of Hedgehog pathway in cancer is believed to lead to transformation of adult stem cells into cancer stem cells that give rise to the tumor.

As an inhibitor of angiogenesis and Hedgehog pathway, Itraconazole should lead to both inhibition of tumor growth and metastasis. The inhibition of these mechanisms are expected to take place at drug doses normally used in humans for anti fungal treatments. Indeed, as discussed below there are already a few case reports published where Itraconazole has been shown to induce tumor size reduction in e.g. pancreatic cancer and prostate cancer. However, there are multiple reports in literature indicating its relevance for most tipes of cancers including but not limited to

  • prostate (Ref.),
  • lung (Ref.),
  • basal cell carcinoma (Ref.),
  • ovarian (Ref.),
  • breast – triple negative(Ref.),
  • adrenal (Ref.),
  • brain (Ref.),
  • pancreatic(Ref.),
  • biliary tract cancer (Ref.),
  • etc.

Note that the AnticancerFund foundation has published recently a comprehensive article dedicated to the anti cancer action of Itraconazole (Ref.).

Based on all the scientific evidence, including case reports and clinical trials, Itraconazole is a highly relevant anti cancer drug, accessible to all at a low cost. Best is to combine with other anti cancer drugs. I would probably combine it with other angiogenesis inhibitors to enhance the anti angiogenesis effect or with anti cholesterol drugs and supplements (such as HCA, ACAT inhibitors, Statins). Clinical trials are using Itraconazole both as stand alone therapy or combination with chemo (e.g. Ref.)

Case Report in Humans:

Itraconazole therapy in a pancreatic adenocarcinoma patient: A case report. http://www.ncbi.nlm.nih.gov/pubmed/25670260

This report refers to a 64-year-old male was diagnosed with Stage III locally advanced unresectable pancreatic adenocarcinoma. The patient was treated with radiation plus chemotherapy, which included cisplatin and capecitabine but the patient’s tumor remained unresectable; therefore, palliative chemotherapy treatments were initiated, which included gemcitabine and erlotinib. After two gemcitabine cycles, he was admitted to the hospital because of loss of motor function due to spinal cord hemisection. After the surgery, the patient became neutropenic because of previous chemotherapy cycle and developed disseminated histoplasmosis (infection by a fungus). After he received his nine-month course of itraconazole to address the fungus infection, the pancreatic cancer was readdressed and found to be resectable. The tumor was resected and over the next several years, he showed no evidence of pancreatic metastases or relapse. The treating physicians assessed that the reduction in pancreatic tumour and inhibition of metastasis was due to itraconazole treatment.

Successful treatment of oral itraconazole for infantile hemangiomas: A case series http://onlinelibrary.wiley.com/doi/10.1111/1346-8138.12724/full

Infantile hemangiomas can present a therapeutic challenge to clinicians, especially when associated with severe pain and feeding difficulties. The standard therapeutic management includes corticosteroids and propranolol. However, the clinical response is not always satisfactory. We present six cases of infantile hemangiomas successfully treated with oral itraconazole approximately 5 mg/kg per day. In the first month, the red color of the lesions became a little lighter and the growth of the lesions was controlled in all cases. An obvious clinical improvement was noted in all cases during the 3-month period, with 80–100% improvement in each patient at the end of the treatment, which was judged by both their parents and the dermatologists. Compliance with treatment instructions of oral itraconazole in infants was judged to be very good. Side-effects were mild and limited. Although itraconazole can inhibit angiogenesis and tumor growthin vitro and in vivo associated with some cancers, further research is required to understand the pathogenesis of infantile hemangiomas and the mechanism of itraconazole.

High-dose itraconazole as a non-castrating therapy for a patient with biochemically-recurrent prostate cancer http://europepmc.org/articles/PMC3959234/

A 65-year-old man presented with biochemical recurrence of prostate cancer. … he was referred to our institution for non-hormonal management of his biochemically-recurrent prostate cancer, at which time his PSA was 34.3 ng/mL and his PSADT was about 6 months. Due to the patient’s strong desire to avoid castrating therapies, he requested to be treated off-study with high-dose itraconazole based on the results of the prior phase II trial, while he voiced understanding that this study was conducted in a different patient population and that the results may not apply to his current disease state.

At initiation of treatment with itraconazole (300 mg, twice daily), the patient’s PSA level was 34.3 ng/mL and his testosterone level was in the non-castrate range. Given the potential concern for itraconazole-mediated suppression of adrenal cortical function, aldosterone and cortisol levels were also evaluated as were ACTH levels. Following only one month of treatment with itraconazole, the PSA declined to 20.1 ng/mL, while the patient did report some grade-1 fatigue. After three months of treatment, his PSA had declined to 16.2 ng/mL, reflecting a >50% PSA reduction. Importantly, his testosterone levels remained largely unchanged, while DHEA levels increased somewhat. The patient had no clinical or biochemical evidence of adrenal insufficiency or hypocortisolism. Conversely, he developed hypoaldosteronism accompanied by an elevation in ACTH, consistent with the experience from the prior phase II study. After 5 months of treatment, and despite a persistent PSA response with minimal adverse events, the patient developed asymptomatic hyperbilirubinemia necessitating discontinuation of itraconazole. While the bilirubin level normalized after stopping itraconazole, this was accompanied by a subsequent increase in PSA level to 29.4 ng/mL, approximately one month after drug discontinuation. Due to the occurrence of hyperbilirubinemia, further treatment with high-dose itraconazole was discouraged.

Conclusion: In this patient with biochemically-recurrent prostate cancer, off-label treatment with itraconazole (600 mg/day) resulted in a >50% decline in PSA, without evidence of testosterone suppression.

Clinical Trials:

Combination Chemotherapy with Itraconazole for Treating Metastatic Pancreatic Cancer in the Second-line or Additional Setting. http://www.ncbi.nlm.nih.gov/pubmed/26124377

BACKGROUND: We evaluated chemotherapy with itraconazole (a common anti-fungal agent that is a potent inhibitor of the Hedgehog pathway, P-glycoprotein, and angiogenesis) for treating progressive pancreatic cancer.

PATIENTS AND METHODS: We retrospectively reviewed the medical charts of patients with histologically-diagnosed pancreatic cancer who had received first- or second-line chemotherapy and subsequent chemotherapy with itraconazole.

RESULTS: A total of 38 patients received docetaxel (35 mg/m(2)), gemcitabine (1,000 mg/m(2)), and carboplatin (area under the curve, 4 mg/min/ml) on day 1 and oral itraconazole solution (400 mg) on days -2 to 2, repeated every 2 weeks. One complete response and 13 partial responses were observed, for a response rate of 37%. Eight (21%) patients experienced febrile neutropenia. The median overall survival was 11.4 months (95% confidence interval=8.5-21.2 months).

CONCLUSION: Combination chemotherapy with itraconazole is promising for prolonging overall survival, with acceptable toxicities in the second-line setting of pancreatic cancer.

Impact of Itraconazole After First-line Chemotherapy on Survival of Patients with Metastatic Biliary Tract Cancerhttp://www.ncbi.nlm.nih.gov/pubmed/26254389

AIM: We evaluated the efficacy and safety of itraconazole after first-line chemotherapy in patients with metastatic biliary tract cancer (BTC).
PATIENTS AND METHODS: We retrospectively reviewed data from patients with histologically-diagnosed BTC with distant metastases who had received one or more lines of chemotherapy and subsequent itraconazole chemotherapy.
RESULTS: Among 28 enrolled patients, 26 (93%) received docetaxel (35 mg/m(2)), gemcitabine (1,000 mg/m(2)), and carboplatin (AUC4) on day 1 and oral itraconazole solution (400 mg) on days -2 to 2, repeated every 2 weeks. Two patients received docetaxel plus itraconazole with irinotecan. Two complete responses and 14 partial responses were observed, with a response rate of 57%. The median overall survival was 12.0 months. During 160 cycles, 21 (75%) and 17 (61%) patients had grade 3/4 neutropenia and thrombocytopenia, respectively. Two patients (7%) experienced febrile neutropenia.
CONCLUSION: Combination chemotherapy with itraconazole after first-line chemotherapy is promising for patients with metastatic BTC.

Repurposing Itraconazole as a Treatment for Advanced Prostate Cancer: A Noncomparative Randomized Phase II Trial in Men With Metastatic Castration-Resistant Prostate Cancer http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3579600/

The high-dose arm enrolled to completion (n = 29), but the low-dose arm closed early (n = 17) because of a prespecified futility rule. The PPFS rates at 24 weeks were 11.8% in the low-dose arm and 48.0% in the high-dose arm. The median PFS times were 11.9 weeks and 35.9 weeks, respectively. PSA response rates were 0% and 14.3%, respectively. In addition, itraconazole had favorable effects on CTC counts, and it suppressed Hedgehog signaling in skin biopsy samples. Itraconazole did not reduce serum testosterone or dehydroepiandrostenedione sulfate levels. Common toxicities included fatigue, nausea, anorexia, rash, and a syndrome of hypokalemia, hypertension, and edema. High-dose itraconazole (600 mg/day) has modest antitumor activity in men with metastatic CRPC that is not mediated by testosterone suppression.

Impact of Combination Chemotherapy with Itraconazole on Survival of Patients with Refractory Ovarian Cancer http://ar.iiarjournals.org/content/34/5/2481.abstract

Conclusion: Adjunctive itraconazole is promising for patients with refractory ovarian cancer.

Topical Itraconazole in Treating Patients With Basal Cell Cancer https://clinicaltrials.gov/ct2/show/NCT02735356

A Case Study of the Effects of Topical Itraconazole on Pharmacodynamic Modulation of Hedgehog Target Gene Expression in Basal Cell Carcinomas in Patients

More clinical trials involving Itraconazole are discussed in this reference: Ref.

Mechanism:

Antiangiogenic activity due to inhibition of mTOR.
mTOR inhibition is mediated by:

  • the inhibition of cholesterol trafficking through the endolysosome – cholesterol biosynthesis is also essential for endothelial cell growth.
  • itraconazole binds directly to voltage-dependent anion channel 1 (VDAC1) and interferes with its primary cellular function of regulating mitochondrial metabolism, causing a drop in cellular energy levels that triggers the energy-sensing protein AMP-activated protein kinase (AMPK) which down-regulates mTOR (Ref.)

ultimately leading to inhibition of endothelial cell proliferation and with this antiangiogenic activity.

  • Next to this, it has also be found as a potent inhibitor of Hedgehog (Hh) pathway activity. (Ref.)

Itraconazole mechanisms

The figure above is from Reference: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081601/figure/F1/

–> Inhibition of cholesterol transport: Cholesterol is an essential component of cellular membranes and plays a key role in membrane permeability and fluidity. Next to this physical role, it also functions in intracellular transport and cell signaling. Cholesterol can be produced in the cell or absorbed from diet into the serum and further delievered within the body. Serum cholesterol is delivered throughout the body in the form of low-density lipoprotein (LDL) and transported into cells via the LDL receptors (through receptor-mediated endocytosis). Endocytosed LDL is transported to the late endosomes and Cholest Transportlysosomes where cholesteryl esters are hydrolyzed and free cholesterol is released from the endosomal system for delivery to other compartments within the cell, including the plasma membrane and endoplasmic reticulum. One of the most important machineries of cholesterol trafficking in the endosomes and lysosomes is the Niemann-Pick, type C (NPC) proteins (NPC1 and NPC2), which help the hydrolysis of cholesteryl esters and deliver free cholesterol out of the endolysosomes. (Ref.) Inhibition of NPC1 or 2 causes accumulation of cholesterol and glycolipids in the endosomes and lysosomes. Itraconazole inhibits cholesterol trafficking and induces accumulation of cholesterols in the organelle (NPC-like phenotype in endothelial cells) and as a result inhibits mTOR activity in endothelial cells and VEGFR2 signaling pathway (Ref.). Thus, interfering with cholesterol trafficking in endothelial cells and that cholesterol trafficking is a novel target for anti-angiogenesis therapy. (Ref.)

The figure above is from Reference: http://atvb.ahajournals.org/content/24/7/1150.full

Here is a very good paper on Cholesterol transport within cells. http://atvb.ahajournals.org/content/24/7/1150.full And here is another good one but older http://www.jbc.org/content/270/26/15443

–> Inhibition of Hedgehog pathway: itraconazole, was identified as a potent inhibitor of Hh pathway activity with an IC50 of approximately 800 nM which is lower than that achieved in humans at normal daily dose (see Pharmacokinetics section) (Ref.) Activation of the hedgehog pathway has been implicated in the development of cancers in various organs, including brain, lung, mammary gland, pancreas, adrenal, prostate and skin. Basal cell carcinoma, the most common form of cancerous malignancy, has the closest association with hedgehog signaling. Abnormal activation of the pathway is believed to lead to development of disease through transformation of adult stem cells into cancer stem cells that give rise to the tumor. Cancer researchers hope that specific inhibitors of hedgehog signaling will provide an efficient therapy for a wide range of malignancies. Drugs that specifically target Hedgehog signaling to fight this disease are being actively developed by a number of pharmaceutical companies (Ref.1, Ref.2).

Note: Imiquimod, previously discussed on this website has also Hedgehog inhibiting properties (Ref.)

Besides the above mechanisms, Itaconazole is also believed to work against multi-drug resistance (MDR) which is highly expressed in many tumors. It is also an autophagy inducer. Itraconazole-induced autophagy is mediated by abnormal cellular cholesterol redistribution and subsequent inhibition of the AKT1-MTOR signaling pathway.  (Ref.1, Ref.2).

Administration and Dose:

Commonly administered orally, either as 100 mg or 200 mg capsules or as oral solution.

Itraconazole is already approved by the U.S. Food and Drug Administration (FDA) as an antifungal agent at oral doses in the range of 200–600 mg/day. This is also the dose range used in clinical trials.  200 mg might be sufficient to inhibit both angiogenesis (Ref.) and Hh pathway (Ref.)

Here is another administration strategy where Itraconazole is combine with Chemo. The strategy seems clever: http://www.ncbi.nlm.nih.gov/pubmed/26124377

I would probably use it in cycles, two weeks on and two weeks off, 200mg 2x/day at 12 hours distance with food.

Antagonists:

I would not combine Itraconazole with autophagy inhibitors (Ref.)

Safety and Toxiciy:

Although itraconazole has been associated with rare cases of hepatotoxicity as its major side effect, it can be taken orally for up to 3 months to treat finger and toenail infections.

In a clinical trial common toxicities included fatigue, abdominal pain, nausea and constipation (Ref.)

Although generally well-tolerated, caution is advised with patients at high risk of heart failure or impaired hepatic function.

Several case reports have identified itraconazole-enhanced chemotherapy toxicity, especially in association with vincaalkaloid chemotherapy. (Ref.)

Coadministration of simvastatin (or lovastatin) with antifungals (itraconazole or ketoconazole) can result in rhabdomyolysis and acute renal failure (Ref.) Simvastatin & lovastatin should therefore not be used concomitantly with itraconazole and other potent CYP3A4 inhibitors, or the dosage of lovastatin should be greatly reduced while using a CYP3A4 inhibitor (Ref.). This increased toxicity is not apparent with fluvastatin (Ref.)

Pharmacokinetics:

  • A single 200 mg dose, taken with food, produces an average peak plasma concentration of 239 ng/mL (0.34μM) within 4.5 hours, whereas at steady state (after 14 days of 200 mg every 12 hours), the average plasma concentration is 1881 ng/mL (2.67 μM).
  • The plasma half-life of 200 mg of the capsule form is 24 hours at steady state.
  • The mean absolute bioavailability is around 55%, and as a highly lipophilic molecule ITZ has a high affinity for tissues, achieving concentrations two to ten times higher than those in plasma.
  • Tissue penetration of antifungals: http://www.ncbi.nlm.nih.gov/pubmed/24396137
  • Oral absorption of itraconazole is reduced when gastric acid production is decreased, by e.g. H2 receptor agonists (such as cimetidine or ranitidine) or proton pump inhibitors (e.g. omeprazole or pantoprazole)
  • is a potent inhibitor of cytochrome P450 (CYP) 3A4 –> check interaction with currently used drugs before administration

Reference for the above points on pharmacokinetics: Ref.

Off target effects:

Low-dose and high-dose itraconazole appeared to slightly increase serum testosterone and DHEA-S levels, respectively. Additionally, high-dose (but not low-dose) itraconazole potently suppressed serum aldosterone while raising plasma ACTH (Ref.1, Ref.2). There were no effects with either itraconazole dose on serum cortisol at 4 weeks or 12 weeks.

Source:

Itraconazole is usually supplied as 100- or 200-mg capsules and can be found at the pharmacy in probably any country, e.g. http://www.buy-pharma.co/Generic-Sporanox-Itraconazole-Capsule-p-194.html

References:

Intracellular Cholesterol Transport http://atvb.ahajournals.org/content/24/7/1150.full

Intracellular cholesterol transport is essential for the maintenance of cholesterol homeostasis. Many aspects of cholesterol metabolism are well-known, including its synthesis in the endoplasmic reticulum, its extracellular transport in plasma lipoproteins, its uptake by the low-density lipoprotein receptor, and its regulation of SREBP and LXR transcription factors. These fundamental pathways in cholesterol metabolism all rely on its proper intracellular distribution among subcellular organelles and the plasma membrane. Transport involving the ER and endosomes is essential for cholesterol synthesis, uptake, and esterification, whereas cholesterol catabolism by enzymes in mitochondria and ER generates steroids, bile acids, and oxysterols. Cholesterol is a highly hydrophobic lipid that requires specialized transport in the aqueous cytosol, involving either vesicles or nonvesicular mechanisms. The latter includes hydrophobic cavity transporters such as StAR-related lipid transfer (START) proteins. Molecular understanding of intracellular cholesterol trafficking has lagged somewhat behind other aspects of cholesterol metabolism, but recent advances have defined some transport pathways and candidate proteins. In this review, we discuss cholesterol transport among specific intracellular compartments, emphasizing the relevance of these pathways to cholesterol homeostasis.

Repurposing Drugs in Oncology (ReDO)—itraconazole as an anti-cancer agent http://ecancer.org/journal/9/full/521-repurposing-drugs-in-oncology-redo-itraconazole-as-an-anti-cancer-agent.php

Itraconazole, a common triazole anti-fungal drug in widespread clinical use, has evidence of clinical activity that is of interest in oncology. There is evidence that at the clinically relevant doses, itraconazole has potent anti-angiogenic activity, and that it can inhibit the Hedgehog signalling pathway and may also induce autophagic growth arrest. The evidence for these anticancer effects, in vitro, in vivo, and clinical are summarised, and the putative mechanisms of their action outlined. Clinical trials have shown that patients with prostate, lung, and basal cell carcinoma have benefited from treatment with itraconazole, and there are additional reports of activity in leukaemia, ovarian, breast, and pancreatic cancers. Given the evidence presented, a case is made that itraconazole warrants further clinical investigation as an anti- cancer agent. Additionally, based on the properties summarised previously, it is proposed that itraconazole may synergise with a range of other drugs to enhance the anti-cancer effect, and some of these possible combinations are presented in the supplementary materials accompanying this paper.

Itraconazole Inhibits Angiogenesis and Tumor Growth in Non–Small Cell Lung Cancer http://cancerres.aacrjournals.org/content/71/21/6764.abstract

The antiangiogenic agent bevacizumab has been approved for the treatment of non–small cell lung cancer (NSCLC), although the survival benefit associated with this agent is marginal, and toxicities and cost are substantial. A recent screen for selective inhibitors of endothelial cell proliferation identified the oral antifungal drug itraconazole as a novel agent with potential antiangiogenic activity. In this article, we define and characterize the antiangiogenic and anticancer activities of itraconazole in relevant preclinical models of angiogenesis and lung cancer. Itraconazole consistently showed potent, specific, and dose-dependent inhibition of endothelial cell proliferation, migration, and tube formation in response to both VEGF- and basic fibroblast growth factor–mediated angiogenic stimulation. In vivo, using primary xenograft models of human NSCLC, oral itraconazole showed single-agent growth-inhibitory activity associated with induction of tumor hypoxia-inducible factor 1 alpha expression and marked inhibition of tumor vascularity. Itraconazole significantly enhanced the antitumor efficacy of the chemotherapeutic agent cisplatin in the same model systems. Taken together, these data suggest that itraconazole has potent and selective inhibitory activity against multiple key aspects of tumor-associated angiogenesis in vitro and in vivo, and strongly support clinical translation of its use. Based on these observations, we have initiated a randomized phase II study comparing the efficacy of standard cytotoxic therapy with or without daily oral itraconazole in patients with recurrent metastatic NSCLC.

Clinical Implications of Hedgehog Pathway Signaling in Prostate Cancer http://www.mdpi.com/2072-6694/7/4/0871/htm

Activity in the Hedgehog pathway, which regulates GLI-mediated transcription, is important in organogenesis and stem cell regulation in self-renewing organs, but is pathologically elevated in many human malignancies. Mutations leading to constitutive activation of the pathway have been implicated in medulloblastoma and basal cell carcinoma, and inhibition of the pathway has demonstrated clinical responses leading to the approval of the Smoothened inhibitor, vismodegib, for the treatment of advanced basal cell carcinoma. Aberrant Hedgehog pathway signaling has also been noted in prostate cancer with evidence suggesting that it may render prostate epithelial cells tumorigenic, drive the epithelial-to-mesenchymal transition, and contribute towards the development of castration-resistance through autocrine and paracrine signaling within the tumor microenvironment and cross-talk with the androgen pathway. In addition, there are emerging clinical data suggesting that inhibition of the Hedgehog pathway may be effective in the treatment of recurrent and metastatic prostate cancer. Here we will review these data and highlight areas of active clinical research as they relate to Hedgehog pathway inhibition in prostate cancer.

Disclaimer:

This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual. Through this site and linkages to other sites, I provide general information for educational purposes only. The information provided in this site, or through linkages to other sites, is not a substitute for medical or professional care, and you should not use the information in place of a visit, call consultation or the advice of your physician or other healthcare provider. I am not liable or responsible for any advice, course of treatment, diagnosis or any other information, services or product you obtain through this site. This is just my own personal opinion regarding what we have learned on this road.

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29 thoughts on “Itraconazole: An Antifungal Drug With Anti Cancer Properties

  1. A couple of observations. The usability of itraconazole for brain cancer is highly debatable. The article cited proved that it is effective in vitro and in subcutaneous xenografts, but penetration into CSF (from oral or injectable administration) is poor and variable, so I wouldn’t recommend it for brain cancer.
    While it has been proposed as a substitute for ketoconazole in the CUSP9 –> CUSP9* protocols, this poor penetration (probably due to the very high protein binding) into CSF seems to have been omitted. Direct delivery of itraconazole into CSF may be effective though, but I found no reference, and there is some research into nano-formulations that could improve CSF concentration.
    There is also the issue of interaction with many other medications, but there is a possible replacement, posaconazole (it is about 7 times more expensive though).
    Posaconazole, a Second-Generation Triazole Antifungal Drug, Inhibits the Hedgehog Signaling Pathway and Progression of Basal Cell Carcinoma.
    http://www.ncbi.nlm.nih.gov/pubmed/26823493

    Regarding lung cancer, the combination therapy with pemetrexed looks promising, although it is only palliative.
    Phase 2 study of pemetrexed and itraconazole as second-line therapy for metastatic nonsquamous non-small-cell lung cancer.
    http://www.ncbi.nlm.nih.gov/pubmed/23546045

    1. Thanks for the additions Ovidiu.

      I like Itraconazole due to its well established safety profile during 30 years and interaction with cholesterol transport. And I do not like that it has side effects. But these side effects are acceptable for anti fungal treatments and incomparable with chemo.
      Posaconazole:
      – is new with a safety profile that still has to be proven (besides statements such as that in the abstract of the paper)
      – the side effects seem ti be similar with Itraconazole https://www.stjude.org/content/dam/en_US/shared/www/patient-support/med-cards/posaconazole.pdf
      – I cannot find anything that indicates the influence on cholesterol transport

      Therefore, to me Posaconazole is interesting but still too new and its action against various cancers remains to be demonstrated.

      Do you have the complete paper at the link you sent me http://mct.aacrjournals.org/content/15/5/866 or only the abstract? If you have the full paper, can you please send it to me? Thanks.

    1. Hi Andreas,

      That is unclear, but it seems that may be possible. Not enough literature on that. I will go deeper in that when I will write on Omeprazole but for not, this statement: “In light of the reported ability of PPI to revert chemoresistance of tumour cells,19, 26, 29 it is conceivable that this effect may be mediated by the inhibition of autophagy that we described here.” http://www.nature.com/cddis/journal/v1/n10/full/cddis201067a.html

      1. Ok My father got the terrible pancreatic cancer. And my idea was to copy the strategy of the clinical trial you mentioned, the interval of intraconazole two days before and two days after chemo. But my idea was also to use omeprazole , in pancreatic cancer and I suppose other cancers to there are so called helper cells , that helps the cancer survive chemo, exsosomes. I read that those are partly driven by the H+ atp channels in the cancer cell. So I looked that up if omeprazole could counteract that. And it seems in vitro studies that exsosomes and acidification decreases with omeprazole . And as a consequence higher amount of chemo reach the tumorcell. That’s why it is a tempting idea to use omeprazole together with intraconazole. But if they counteract eatchother I think I will just go with the intraconazole ( Hca as you recommended , and curcumin for the anti angionetic properties.)

        All the things I wrote could be wrong , English is not my mother tongue and I’ v could have misunderstood what I’ve read. Next time I will not rely on my memory I will post the sources.

        1. Hi Andreas,

          For a good supporting strategy for chemo, I would recommend looking at this: https://www.cancertreatmentsresearch.com/if-chemotheraphy/

          There are several drug resistance mechanisms that would be good to address. One of them is the acidity around the tumors that can be addressed with Proton pump inhibitors and possibly other drugs (see discussion here https://www.cancertreatmentsresearch.com/ph-cancer-a-top-treatment-strategy/). Omeprazole is a proton pump inhibitor that can contribute to reducing acidity around the tumors. Lanzoprazole seems to be even more effective compared to Omeprazole. Normally, proton pump inhibitors should work well with Itrzconazole since they are also inhibiting autophagy. Here is a paper explaining how they inhibit autophagy: “Because of their effects to raise endosomal pH, PPIs also inhibit autophagy” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4638015/

          As discussed in my post https://www.cancertreatmentsresearch.com/if-chemotheraphy/ another resistance mechanism is due to the fact that the tumor vessels are not easy accessible for the chemo. That is why just drinking some coffee before chemo should help chemo rich better the tumor.

          Strong antioxidants should also be avoided and using Paracetamol before during chemo should help reduce the anti oxidant level so that the cancer cells have less chance to survive chemo.

          Kind regards,
          Daniel

  2. Thank you Daniel for pointing my attention to this article.
    I did read it in the past 🙂 I just find it very interesting now as my mom reports feeling better with each pill she takes.
    Good thing i browsed what the oncologist was giving her, i was curious to see what made her feel better, and when looking in the vials bag i spotted a few itraconazole pills that caught my attention since the others were, Vit B1, B12, Omeprazole, Algocalmin and a few others.
    Itraconazole also caught my attention because i remembered it being talked about in here, but yes i forgot about the article for it.
    For now my mom is taking 1 pill of 100mg / day, silimarin 1000mg+colina

    What drugs should it be synergistic with? Basic and non-basic.
    I got Tarceva 150mg pills…..

    This should serve as another reminder that the simple things can sometimes surprise us in a nice way.
    I think it is unfortunate that the oncologist ignored what my mom said to her about continuing treatment at home because she was feeling better, it makes me wonder, who is ignorant, her or us. Maybe she has no expectation from the drugs she is giving to the patients, and to be honest neither did i, but when you hear someone saying “hey, something is working here, we should do this more often, at home” would it hurt to pay attention and maybe hope? It could be that after more than 30 years of oncology, working out of retirement and age itself could play a role in her behavior as a doctor.

    Anyway, thank you very much, grab a beer and enjoy the sunshine this weekend.
    Alex

    1. Hi Alex,

      The reality is that the only chance for real value added to cancer patients comes from new perspectives. If the current perspectives would work we would not have this discussion here. Unfortunately, regardless of the country we live in, the world succeeded to build globally a framework for doctors such that they do not have the time and are not requested to have an open mind for uncovering new patterns and with that new understandings. With the exception of the academic hospitals, the role of the medical doctor is to find a diagnostic and give to the patient a drug that is known to work for that illness. They are doing this from early morning to late evening as there are too many patients. Anyone in their place will probably close their mind and focus on applying what they already know due to time constrains. So the questions is what can we do to help them be able to help more? What should we change and how? That is what I am thinking and would like to address with the foundation.

      Kind regards,
      daniel

    2. @Alex: it would be useful to find out why the oncologist gave your mother Itraconazole, for anti-angiogenic treatment (which is mild and OK IMO), or for a fungal infection.
      In case it’s for a fungal infection, where is it? It is strange that your mother got better so soon, and it seems because of Itraconazole. There is a remote possibility that the spine problem is not caused by the cancer, but by a fungal infection (Candida or Aspergillus).

      1. Ovidiu.
        It looks like itraconazole was given to her for the side effects on her skin where she is more sensitive, the side effects are caused by erlotinib.

        Thankfully my mother is feeling better these days, she took itraconazol for more than 2 weeks, she no longer needs oxigen and some of her left arm movement is back, all this at a very slow pace of recovery if it can be called that.
        I admit she started taking tarceva again, every other day because i insisted, the doctor said to stop tarceva again todday, but i disagreed and advised my mother to continue taking tarceva every other day, being scared of what happened last time she listened to the doctor, and she stopped then, so we ended up in the clinic for a few weeks. I thouht that was the end for her, but that itraconazole really changed the game sorta speak, indeed slowly and very hard to notice.
        So we are outside what the doctor is saying now.
        She had zometa again today in iv.
        I hope i have enough time to ponder….. i know something must be done, but it is obvious the oncologist will not help with anything outside of protocol. It is still possible she will wish to change to gefitinib but who knows how much time that will take and i don’t have any expectations from gefitinib, or should i?
        So i think of what i should do, in a manner that it won’t harm her, because…. sadly at this time, i am no doctor.
        When talking to the oncologist she said that the problem is of oncologic nature, and that the “new” thing is somewhere at C5 on the spine affecting her arms, chest and my mom says it extents all the way to her mouth, a sort of neuropatic, something tells me this is nothing new but only manifested itself highly evident because tarceva was stopped then, inflamation etc.

        They had her on dexamethazone, b12, b6, b1, omeprazole iv and others…
        but the itraconazole pills stood out to me

        I am thinking about 2dg to be added into this mix, but i am not sure if it would be a good thing to do in theory let alone in practice.
        Does this thing have no weakness?

        Also, i personally feel and believe my mother’s cancer has innate mutations that help it thrive and survive in almost any situation. If it didn’t it would have been gone by now, so i feel. I think that any easy disease would have been cured by now with surgery and the drugs she took all this time. But since the disease is here still, points to a high level of adaptability in my mind.
        Good news tho, there are no distant metastasis, not to brain or other organs.
        However i may have forgotten to say this plenty of times, she does have adrenal glands adenomus nodules bilateral, they are slightly smaller when compared to the last scan.
        These nodules may be connected to the disease somehow, i don’t know.

        Looking forward for your thoughts.
        Alex

        1. @Alex: that low dose Itraconazole made a difference, still make me suspect a fungal infection, possibly candidiasis. That the affected vertebra is C5 (in the neck, right?), is also odd, I would have expected metastasis to thoracic vertebrae. However, Itraconazole has poor bone penetration, so either for cancer or fungal infection in bone tissue, it’s not very helpful.
          In principle, azoles inhibit Erlotinib metabolism, leading to higher plasma concentration of Erlotinib, and worse side effects, so the combination is not recommended. Omeprazole lowers Erlotinib absorbtion, so the combination is also not recommended. I searched for some article that would discuss mitigation of Erlotinib skin adverse effects by Itraconazole, and found none. Doxycycline (at 100 mg daily) appears to lower the severity of those adverse effects.
          Doxycycline for prevention of erlotinib-induced rash in patients with non-small-cell lung cancer (NSCLC) after failure of first-line chemotherapy: A randomized, open-label trial.
          PMID: 26946985

          Assuming the C5 problem is caused by metastasis, Itraconazole might help lower Erlotinib resistance, through Hedgehog inhibition.
          Efficacy of continuous EGFR-inhibition and role of Hedgehog in EGFR acquired resistance in human lung cancer cells with activating mutation of EGFR.
          PMID: 28416737

          Chloroquine may also help reverse resistance to Erlotinib in bone tissue, due to autophagy inhibition, which leads to decreased hypoxia (bone metastases are hypoxic, and this activates Stat3 and Erlotinib resistance). Chloroquine is also a weak Stat3 inhibitor and strong Hedgehog inhibitor.

          About 2DG, in vivo it’s antagonistic with Erlotinib, but this might be reversed by chloroquine.
          2-Deoxy-d-glucose Suppresses the In Vivo Antitumor Efficacy of Erlotinib in Head and Neck Squamous Cell Carcinoma Cells.
          PMID: 27178822

          1. Thank you very very much Ovidiu for all the time you put into your replies.
            As far as i deduce, since the oncologist said this is a oncologic problem, the issue is indeed a metastasis to C5 in the neck as you said, affecting the medula, mainly on the left side.
            After erlotinib stopped, a few days went by apparently normal, but.
            Chills, shock, and then quick degeneration of nervous functions visible as follows:
            Left eye drooping, sleepiness, difficulty breathing, left arm useless, right arm hardly any movement in fingers.
            Indeed things have improved after all the clinic thing and itraconazole.
            The root of the problem was originally on the exterior of the right superior pulmonary lobe and has extended to the outside of that trough the pleura and then to spine bone and inside the medulla canal, pressing against it and maybe also invading it.
            However, surgery was performed and a part of the lung with the bulk of the tumor was removed, but what remained was the part inside the spine tissue, and that has over time caused paralysis and now is causing damage over larger areas, mainly on bone and nervous system, and doesn’t appear to travel to distant places or other organs, so far. It creeps along and maybe condensates here and there, treatment appears to have cut down on some of it but has allowed the other parts of the tumor to do as they please.
            The oncologist once again suggested that the treatment be stopped because of the skin issues, i went against that decision and insisted that my mother takes at least 1 pill every other day.
            After what happened last time i feel it would be unwise to not be insistent about it, and seeing how it went last time, going against my suggestion, she now approved, but to what cost? My dear what cost.
            Every time i go there i feel i am going in hell, my head goes into the ground as i walk that street.
            Nobody deserves this, let alone mother or i.
            So she takes the pills we still have, till the doctor decides to do anything….
            Most likely will give her gefitinib instead of tarceva as she said to me. And i don’t have expectations of any kind, or am i wrong and should have expectations? I doubt the answer is yes but if so, please say.
            My mother’s nervous and circulatory system is much weakened, i don’t know what i should do if anything at all.
            Sorry for making it long yet again.

            What do you make of all this?
            What is there left on the table?

            I need something that will clear out a big chunk of the tumor with some speed, allowing for her nervous system to regain some strength.
            The speed should be a month or two.
            These drugs are making my mom’s body decay slowly, to not much avail, making her much, much less able to cope with any promising treatment should it come. Almost guaranteeing failure.

            Thank you very much once again.
            Alex

            1. @Alex: I wish you had something to thank me for, but there aren’t new treatment options that I’m aware of.
              I will try to find something potentially helpful over the next days, but I am afraid there aren’t many that I didn’t find yet. Unfortunately, without knowing the mutations that the vertebra metastasis harbors, it’s almost impossible to recommend an effective treatment, since there are so many possibilities.

              Switching to Gefitinib is probably going to lower the skin adverse effects, but not a lot. I would not expect to do better than Erlotinib against cancer.
              An alternative to Zometa would be Denosumab (more expensive), but I don’t know how much more effective it would be against the bone metastasis. Maybe the oncologist could order a blood test to decide this.
              Denosumab has a higher risk of osteonecrosis of the jaw, but does not affect the kidneys (Zometa does affect them).

            2. @Alex: I tried to find something useful, specific for bone metastasis from lung cancer. But couldn’t find much, since bone metastasis from lung cancer is less common than from breast or prostate cancers, and there are less articles on it. I found that it’s somewhat different from those other two, bone metastases from prostate cancer are osteoblastic, from breast cancer are mixed osteoblastic / osteolytic, and from lung cancer mostly osteolytic (osteoclast-driven). Do you have specific information about the C5 vertebra metastasis, of which type it was identified (osteoblastic or osteolytic)?
              It seems all bone metastases occur through the bone marrow, and for osteoblastic ones they are initiated by cancer cells with osteoblast-like properties, but this is not so sure for lung cancer.
              If I understood correctly, the EGFR mutation was confirmed from the resected lung tumor, but not from the C5 vertebra metastasis. Can you confirm this?
              In this case, while the EGFR mutation is probably still present in the metastasis, there could be other mutations that didn’t respond well to the current treatment.
              I am thinking in particular of an Estrogen Receptor mutation, this seems to be favoring bone metastasis in women.

              As I mentioned before, the main palliative options for bone metastasis are local surgery, ablation, or stereotactic radio-surgery. Magnetic Resonance-Guided Focused Ultrasound gives also similar results to radio-surgery.
              The RANKL inhibitor Denosumab gives on average better results than Zoledronic acid, but is a lot more expensive, and it would work best if a blood test (AFAIK not done in Romania) for RANKL would be conclusive.

              I only found one other option that might help, mainly with pain reduction, a radio-pharmaceutical Strontium-89 chloride, which is given IV each 3-6 months. It accumulates in bone, and better in bone metastases, and might be synergetic with Zoledronic acid. But it’s more effective in breast and prostate cancers than in lung.

              Tumoricidal effect and pain relief after concurrent therapy by strontium-89 chloride and zoledronic acid for bone metastases.
              PMID: 29550842
              Comparison of the efficacy of strontium-89 chloride in treating bone metastasis of lung, breast, and prostate cancers.
              PMID: 29578147

            3. Thank you Ovidiu for everything.
              I’m back…

              After a closer look at the scan papers it looks that the C5 area of her spine is not being affected by a tumor.
              Apparently the oncologist lied……

              “Osteofitoza Posterioara C5-C6, C6-C7, la nivel C5 ocupa spatiul lichidian premedular si foramenul stang”

              I have observed a greater speed of accumulation of Erlotinib by seeing how fast the side effects on the skin appear.
              There appears to be a higher toxicity together as my mother’s appetite drops when both are combined (erlotinib+itraconazole)
              Still i am uncertain if the combination did something good, against cancer.
              I’m unable to give you more information because, i don’t have it.
              I confirm that the testing they did was on the lung tumor with all the tissues around it, Pleura, Bone, Lung, Lymph Nodes, etc.

              I am wondering around with my mind, DCA, Erlotinib?
              What can i do to have the tumor die but not swell, so that it causes less damage to the spine and nervous system there.

              Before my mother paralyzed she took DCA for about a month at a rate of 1.5g/day.
              She was feeling great pain back there, CEA levels dropped while CA 19-9 levels increased.
              When we went to have a scan done, her spinal cord was swollen directly in contact with the tumor, and pushed by it.

              I keep wondering, was DCA doing something good there or bad?

              Thanks.
              Alex

            4. @Alex: it’s hard for me to tell if the C5-C7 problem is cancer or not, the term “Osteofitoza” means it’s not cancer, but could be misused. If it’s not cancer, there could be another cause for it, and Itraconazole may help slow the growth of osteophytes. You’ll have to clarify this with the oncologist.
              If it’s cancer, it seems to be osteoblastic (bone-like growth), this is unusual for NSCLC, which usually gives osteoclastic (bone loss) bone metastases. In such a case, I doubt I can find info on treating it like lung cancer, maybe I’ll find something useful searching about treating metastases from prostate cancer (which is osteoblastic).
              Itraconazole is a strong CYP3A4 inhibitor, so it increases the AUC of Erlotinib, not the absorption, and very likely leads to extra liver damage. I suggest to give your mother Liv52 (which is cheap, just make sure it’s not old, or improperly stored) and maybe Essentiale, to protect her liver. I doubt these have any effect on bone metastases.
              About DCA, it is supposed to synergize with Erlotinib against NSCLC with EGFR mutation, but since your mother paralyzed while on DCA, I can’t recommend trying it (could be just a coincidence, or not).

            5. Thank you Ovidiu for the quick reply.

              Looking at the image i believe there is little to no sign of cancerous tumor, the MRI/CT scan results mention none of it.
              I will paste a link here to a slice right trough the middle of the spine http://tinypic.com/r/6p25g9/9 The link will probably expire soon.

              The image dates 9-9-2016 ( the date of the diagnosis ) – about a month before surgery.
              So that’s how the neck spine area looked long before.
              After thinking more about it, i believe now that when my mother did Zometa and the doctor said to STOP Tarceva due to skin side effects, what went on were the following things:
              1 – Cancer and Bone cells responded to Zometa Treatment.
              2 – Tarceva did not have it’s contribution.
              3 – Inflamation due to various reasons

              So it appears to me that the condition was there before, it only worsened now with Zometa, because it doesn’t just cause Osteonecrosis of the jaw, the implications have to be broader, so i think, feel.
              Doesn’t look like it’s osteoblastic. The tumor invades the bone tissue and appears to be replacing it or something like that. So it sounds to me like the cancer metastasis trough invasion of neighbouring bone, pleura, etc tissues is osteoclastic.

              I believe that my mother was suffering from bone/cartilage degeneration long before this cancer appeared, possibly weakened immune system, or some long term deficiencies etc. Romanian life, not the most plentiful when it comes to food and lifestyle.

              As for the liver, my mother takes Silimarin+Colina 1000mg daily. I’ll buy the Liv52 if it adds anything on the table.
              I guess i should get more immune boosting supliments too, but can’t go for bone support due to zometa, calcium.

              Thank you very much.
              Alex

            6. @Alex: based on what you added, I suppose the metastasis is osteolytic, and the osteophytes are something else, possibly worsened by the DCA (kills chondrocytes) and ZOL (combats bone resorption). But if the metastasis is osteolytic, then ZOL still helps with that.
              I wonder if this shouldn’t be treated like a brain metastasis, because the drug penetration into CSF is the problem in both spinal cord and brain mets. In particular, Erlotinib, Gefitinib and Osimertinib have poor penetration into CSF, of 5% or less, so they may not be helping much in this case. There are few reports of Gefitinib and Osimertinib doing better than Erlotinib against spinal metastases from NSCLC, but no clear reasons for the possible benefit.
              There is a newer EGFR inhibitor AZD3759, which has a good penetration into CSF, but won’t be available for your mother soon. A possible treatment option with Erlotinib is pulse dosing, but this still does not achieve good CSF concentration, and may have more side effects. Another option would be intrathecal therapy with Nimotuzumab, which achieves good responses in Leptomeningeal carcinomatosis, but is risky, you should talk to the oncologist about it.

            7. @I don’t know which minerals are going to favor or not your mother’s cancer. I can’t tell if it’s vulnerable, and to which drug, and IMO the oncologist also can’t. To find out such information, a biopsy would be needed, and tested for the current possible mutations.

              ZOL works by inhibiting osteoclasts, which can be used by the cancer to destroy healthy bone.
              Omeprazole may have been given IV (high dose?) to lower the CSF (cerebrospinal fluid) pressure, since it inhibits the production of CSF.

              In my previous comment I mentioned that EGFR TKIs have poor penetration into CSF. Since attacking the tumor from the bone with ZOL and a low dose Erlotinib (in bone) didn’t work for the C5 problem, maybe attacking it from the CSF would be a better option. To increase the Erlotinib concentration into CSF, the pulsed dosing is used, with mixed results. The pulsed dosing may also delay the emergence of resistance, although by now the cancer could have developed a mutation like T790M. Erlotinib is a Pgp substrate and it stimulates Pgp activity, so a Pgp inhibitor like Itraconazole may increase the concentration of Erlotinib into CSF. If the T790M mutation is suspected present, the oncologist could give your mother Osimertinib, which could do better, if it will achieve good concentration in your mother’s CSF. The articles I found mention Osimertinib concentration into CSF between 2% and 16%, so it’s quite variable between patients, possibly because of variable inhibition of Pgp.

            8. Thank you so much Ovidiu for dedicating so much time into the problem.
              The C5 problem doesn’t appear to be of oncological nature. However lower on the spine, at T2-T5 is the infiltrated spine area. So i think the conversation still applies.
              The time to switch to another treatment is coming very soon.
              So what should i ask the doctor to switch to as a most likely best solution in your opinion thus far, accessible in Romania, covered by insurance.
              I believe that whatever is left, and is growing, has some weakness to erlotinib but isn’t being held back 100%, the drug is more of an annoyance to the tumor instead of a real problem….
              The tumor appears to me to have regrown out of the spine from where it was cut, and most likely depends on the spine tissue to obtain nutrients from, perhaps even calcium!?!?. (brings me back to the teeth loss topic raised by me a long time ago)
              There is/are certainly resistance/s of some type/s.
              I stopped mixing itraconazole with tarceva, gave her about a week to recover.
              Added Liv 52, just to make sure things aren’t going too crazy with the liver. (Thank you very much)
              She had Zometa done so Tarceva was added back that same day. 150mg/day.
              Response was, small. (my opinion) I can’t offer any other opinion since nobody bothers to check these things.
              Call me a conspiracy theorist but, sick people don’t pay taxes so…. nobody cares anymore.

              So, list me the options if you will. Please make them idiot proof. Just to make sure I and anyone else would understand them.

              Thank you very much, and take your time with all this. I realize i am not asking easy questions.
              Maybe we should all meet in person?

              Have a great weekend,
              Alex

            9. @Alex: based on what I know, I can’t recommend another regimen, because I wouldn’t be sure at all if it would work better against your mother’s spine metastasis. If another regimen won’t work, then the cancer could quickly kill your mother, by further compressing the spinal cord. The synergy between Zoledronic acid and Erlotinib was reported and confirmed a couple of years ago, and the oncologist was correct prescribing it, but your mother does not seem to be one of the lucky ones with a good response to the regimen.
              I checked again if there’s anything new available, but couldn’t find much. The alternative to ZOL is Denosumab (Xgeva), which is available in Romania, costs about 50% more (regulated price in Romania) than Zometa, and probably covered by insurance (only the oncologist can tell you for sure if a drug is covered by insurance). It improves survival (compared with ZOL) in patients with bone mets from NSCLC, but given after ZOL it increases the risk for osteonecrosis of the jaw.
              Osimertinib is going to do better than Erlotinib if the T790M mutation is present, something that has to be determined (I don’t know how, other than a biopsy). Maybe the oncologist could prescribe Osimertinib just based on the treatment length after which the T790M mutation emerges. But there could be other mutations that confer resistance, and guessing about them would be like throwing dice.
              From the possible chemo adjuvants I mentioned in earlier posts, I suggest to talk to the oncologist about Strontium-89, which might synergize with ZOL. I guess it’s worth trying, just one dose and see if it improves on ZOL.
              And again talk about Sertraline, which can sensitize NSCLC to Erlotinb, even if Kras or T790M mutations are present. Sertraline is extensively distributed, achieves high concentrations in liver, lung and spleen, and may reach good concentrations in CSF and bones. Actually, you can’t take it for very long, because it decreases bone mineral density, by inhibiting both osteoclasts and osteoblasts.
              An alternative to Erlotinib, to allow your mother’s skin to recover, would be metronomic (these drugs are relatively cheap) chemo, that I mentioned earlier, low dose Cyclophosphamide, Etoposide, Celecoxib, and a proton pump inhibitor. You just have to be careful about drug accumulation, possibly because of interaction with other drugs.
              Other agents potentially useful against bone metastases are Crizotinib and Cabozantinib, which could replace Erlotinib if you mother had other known mutations. There’s also Radium-223, which improves survival in patients with BM from prostate cancer, but it’s very expensive.
              A new compound active against bone mets from NSCLC is TAS-115 (I don’t know when it will become available in Romania), which can reverse Erlotinib resistance, inhibits osteoclasts and several kinases, and showed promising results in a mouse model with a Kras mutant, bone-destructing cell line.
              High Potency VEGFRs/MET/FMS Triple Blockade by TAS-115 Concomitantly Suppresses Tumor Progression and Bone Destruction in Tumor-Induced Bone Disease Model with Lung Carcinoma Cells. PMID: 27736957

            10. @Alex: recently an interesting article was published, about synergy between Erlotinib and Sertraline, the anti-cancer activity being mediated by excessive autophagy. The combination appears to be effective against Kras or T790M mutations too, and Sertraline is cheap and achieves good concentrations in cerebrospinal fluid, which might be important against the C5 problem. I suggest to print the article, and discuss it with the oncologist, since buying Sertraline requires a prescription.

              Repurposing sertraline sensitizes non-small cell lung cancer cells to erlotinib by inducing autophagy. PMID: 29875309

  3. After Reading this thread I ´m wandering if Itraconazole ´s ability to reverse some drug´s resistance would apply im my mother´s case. She´s been on Xeloda for the last 8 months. She´s been treating lung metástases from a 2006 breast cancer that returned in 2014. Since last may her markers started raising again and she presents symptoms ( coughing in the mornings), showing that disease doesn´t respond anymore to Xeloda´s treatment. Could itraconazole reverse this kind of situation and make her disease sensible again to Xeloda?

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