Pancreatic cancer: Towards increasing treatment effectivness

17 thoughts on “Pancreatic cancer: Towards increasing treatment effectivness”

1. its crazy how effective LDN + ALA + HCA was in 3 serious cases:
   https://www.ncbi.nlm.nih.gov/pubmed/20042414
   most people with pancreatic do not hear about this treatment. they NEVER get the chance to try it. Sad. Incredibly sad.

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   1. Yes Wondering. That makes me think I should write a post on LDN as well. But like I wrote in one of my posts, my special finding on LDN is that for some it may be good and for others it may be bad.
      The point is that Naltrexone is a TLR4 antagonist. Some cancers may have TLR4 over expressed in which case LDN may help but others have that down regulated. In that case LDN may help the tumor. Here I shortly discussed that https://www.cancertreatmentsresearch.com/acc-adrenocortical/
      Before using LDN I would always check what is known about TLR4 in the specific tumor against which LDN is intended to be used.

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      1. thanks for flagging this….fortunately, in Testicular cancer its overexpressed so i did not do a money waste.
         https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3941388/

         and for pancreatic the same :

         https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024790/

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2. Hi Daniel,

   Yes, you should definitely write a post on LDN (at least I strongly support the idea :-)). What is fascinating to me about it is the fact the low-dose somehow works better than high-dose. It happens rarely for a drug. At least I am not aware of any other that is used this way.

   I found an interesting article on LDN used for rheumatologic purposes: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962576/
   There is some interesting info on microglia information:

   “Naltrexone, however, exerts its effects on humans via at least two distinct receptor mechanisms. In addition to the antagonist effect on mu-opioid and other opioid receptors, naltrexone simultaneously has an antagonist effect on non-opioid receptors (Toll-like receptor 4 or TLR4) that are found on macrophages such as microglia [17]. It is via the non-opioid antagonist path that LDN is thought to exert its anti-inflammatory effects. Microglia are central nervous system immune cells that are activated by a wide range of triggers [18]. Once activated, microglia produce inflammatory and excitatory factors that can cause sickness behaviors such as pain sensitivity, fatigue, cognitive disruption, sleep disorders, mood disorders, and general malaise [19]. When chronically activated, the resulting proinflammatory cascade may become neurotoxic, causing several deleterious effects [20]. Given the wide variety of inflammatory factors produced by activated microglia (e.g., proinflammatory cytokines, substance P, nitric oxide, and excitatory amino acids) [21], a range of symptoms and medical outcomes could share the pathophysiological mechanism of central inflammation.”

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3. After more than 2 years, I’ll try to provide an update on Chemo regimens and possible ways to augment efficacy.
   In 2018 the most effective regimen is still FOLFIRINOX, but it has the highest hematological toxicity and only patients with good performance status get it. GnP is less toxic, but is the most expensive, because of the high cost of Abraxane. A new nano-liposomal formulation of Irinotecan has recently been tried, with good results. Something that should be kept in mind, for patients with locally advanced and unresectable PDAC, but without metastases, is that effective chemo may temporarily shrink the tumor, in which case it could be resected or ablated. As for ablation techniques, recently good results have been achieved with irreversible electroporation, and very recently a new technique, nano-pulse stimulation, similar to IRE but with much shorter pulses, has shown even better results in a mouse model.

   Looking for confirmation of the adjuvants I listed in the original article, there was nothing new on TL-118.
   About phospho-VA, there is a new formulation, but wasn’t tested in combination with Cimetidine. Phospho-valproic acid inhibits pancreatic cancer growth in mice: enhanced efficacy by its formulation in poly-(L)-lactic acid-poly(ethylene glycol) nanoparticles. PMID: 28849098
   About Curcumin, most research is focused on analogues or nano-formulations, but there is one article, with a small improvement over Gemcitabine alone. Phytosome complex of curcumin as complementary therapy of advanced pancreatic cancer improves safety and efficacy of gemcitabine: Results of a prospective phase II trial. PMID: 29614381
   About Tocotrienols, the variable bioavailability seems to have hampered application, but there is research on Gemcitabine – Tocotrienol conjugates.
   About DDW, unfortunately most pancreatic cancers are able to adapt to metabolic changes due to DDW (unlike breast cancer), so it’s not useful here.

   While searching for new treatments against PDAC, I found several new and potent ones, but most are still experimental. I will detail some of them in later posts.

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   1. Regarding ablation techniques, I’ll quote from the articles on Irreversible Electroporation and then Nano-pulse stimulation:

      The application of thermal ablative techniques to LAPC has been previously associated to high rates of morbidity, as a result of a heat sink effect. In LAPC the beneficial effects of ablation is limited by the close proximity of critical vascular structures to the targeted tumor lesions. In fact, the primary mechanism of cell death induced by thermal ablative techniques is represented by a coagulative necrosis that involves also often surrounding structures. Electroporation (IRE) has proved to be a new method of tumor ablation that activates energy-dependent biochemical mechanisms that promote apoptosis. In contrast with other thermal ablative options, IRE has been shown to produce larger perivascular tumor death while sparing tissue scaffolds. The use of IRE in the treatment of LAPC has apparently shown promising results, with relatively acceptable morbidity rates and improvement of survival.

      Irreversible electroporation for locally advanced pancreatic cancer through a minimally invasive surgery supported by laparoscopic ultrasound. PMID: 29335228

      In this study, we assessed nanopulse stimulation (NPS) as a local treatment for pancreatic cancer in a syngeneic mouse Pan02 pancreatic cancer model and characterized corresponding changes in the immune profile. A single NPS treatment either achieved complete tumor regression or prolonged overall survival in animals with partial tumor regression. While this is very encouraging, we also explored if this local ablation effect could also result in immune stimulation, as was observed when NPS led to the
      induction of immune-mediated protection from a second tumor challenge in orthotopic mouse breast and rat liver cancer models. In the Pan02 model, there were insufficient abscopal effects (1/10) and vaccine-like protective effects (1/15) suggesting that NPS-induced immune mechanisms in this model were limited.
      Recently, another electrical engineering technology, which can generate electric pulses with pulse durations in the nanosecond ranges, has been developed by Schoenbach et al. and other groups. Nanosecond pulsed electric fields or electric pulses (nsPEFs or nsEPs), here named Nano-Pulse Stimulation (NPS), have been studied largely for local tumor ablation. Similar to IRE, NPS is delivered with a specialized electrode and is usually considered non-thermal if appropriate parameters are adopted. NPS successfully ablates local tumors with no reoccurrence in several animal models. Beyond the local tumor regression, the protection of no tumor growth from a second tumor challenge was reported from two research groups.

      Nano-Pulse Stimulation for the Treatment of Pancreatic Cancer and the Changes in Immune Profile. PMID: 29954062

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      1. IRE efficacy (in a mouse model, more or less equivalent to LAPC) can be improved by moderate heating of the tumor, quoting:
         Moderate heating (MH) at 43 °C for 1-2 minutes significantly enhanced ex vivo IRE tumor ablation of Pan02 cells by 5.67-fold at 750 V/cm and by 1.67-fold at 1500 V/cm. This amount of heating alone did not cause cell death. An integrated IRE system with controllable laser heating and tumor impedance monitoring was developed to treat mouse ectopic pancreatic cancer. With this novel IRE system, we were able to heat and maintain the temperature of a targeted tumor area at 42 °C during IRE treatment.
         Pre-heating the tumor greatly reduced the impedance of tumor and its fluctuation. Most importantly, MHIRE has been demonstrated to significantly extend median survival and achieve a high rate of complete tumor regression. Median survival was 43, 46 and 84 days, for control, IRE with 100 μs, 1 Hz, 90 pulses and electric fields 2000–2500 V/cm and MHIRE treatment respectively. 55.6% of tumor-bearing mice treated with MHIRE were tumor-free, whereas complete tumor regression was not observed in the control and IRE treatment groups.
         Controllable Moderate Heating Enhances the Therapeutic Efficacy of Irreversible Electroporation for Pancreatic Cancer. PMID: 28924200

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   2. Abraxane (nab-Paclitaxel) is believed to strongly deplete the PDAC stroma, which dense stroma impedes the delivery of chemo to the tumor. However, Abraxane continues to be expensive, and in some countries the high price may prohibit its use. There are some drugs, with anti-fibrotic activity, which could be used for the same purpose, to deplete the PDAC stroma, namely Pirfenidone, Tranilast, and possibly Telmisartan. However, since they are Tgf-beta inhibitors, and Tgf-beta plays a dual role (inhibition or promotion of growth and metastasis), the use of anti-fibrotics listed above should be evaluated on a per patient basis.

      Pirfenidone inhibits pancreatic cancer desmoplasia by regulating stellate cells. PMID: 23348422
      Tranilast-induced stress alleviation in solid tumors improves the efficacy of chemo- and nanotherapeutics in a size-independent manner. PMID: 28393881
      Tumor stromal disrupting agent enhances the anticancer efficacy of docetaxel loaded PEGylated liposomes in lung cancer. PMID: 27171485

      About 80% of the PDAC patients have the Kras mutation, which is associated with resistance to apoptosis (but sensitivity to ferroptosis) and poor response to chemo, but other possible mutations are EGFR (native, about 40% of patients) and Her2 (induced by Gemcitabine). In case of EGFR mutation, addition of Erlotinib to Gemcitabine improves response, especially in patients who develop rash. It may be possible to take advantage of the Her2 upregulation by Gemcitabine, Up-regulation of Her2 by gemcitabine enhances the antitumor effect of combined gemcitabine and trastuzumab emtansine treatment on pancreatic ductal adenocarcinoma cells. PMID: 26475267

      Shikonin appears to be synergetic with Gemcitabine against PDAC, but purified Shikonin is very expensive, and there is no recent trial with the cheap Lithospermum erythrorhizon extract. Shikonin induces apoptosis and necroptosis in pancreatic cancer via regulating the expression of RIP1/RIP3 and synergizes the activity of gemcitabine. PMID: 29312502

      There are a couple of new drugs, that achieve promising results against PDAC, but it’s hard to tell when they will become available to patients. Quoting from articles on Zt/g4-MMAE (RON antibody conjugated to monomethyl auristatin E) and Avasimibe (cholesterol acyltransferase inhibitor):

      In vitro, Zt/g4-MMAE rapidly induced RON internalization, resulting in cell cycle arrest followed by massive cell death. The maximal effect was seen in pancreatic cancer cells with more than 10 000 receptor molecules per cell. Zt/g4-MMAE also synergized in vitro with chemotherapeutics including gemcitabine, 5-fluorouracil, and oxaliplatin to further reduce PDAC cell viability. In vivo, Zt/g4-MMAE exerts a long-lasting activity, which not only inhibited but also eradicated pancreatic xenograft tumors.
      Preclinical Efficacy of Anti-RON Antibody-Drug Conjugate Zt/g4-MMAE for Targeted Therapy of Pancreatic Cancer Overexpressing RON Receptor Tyrosine Kinase. PMID: 29944378

      Single treatment with avasimibe or gemcitabine shows effectiveness in reducing tumor growth rate and induces slight tumor remission after a period of treatment. Tumors grew up again after 20-days gemcitabine treatment, indicating the appearance of gemcitabine-resistance. Avasimibe treatment alone maintains tumor size at a constant level over the treatment period. In contrast, combinational therapy reverses tumor growth by substantially reducing tumor size with no sign of tumor recovery even after 34-days treatment, indicating a nearly complete tumor remission was achieved by the combination therapy.
      Cholesterol esterification inhibition and gemcitabine synergistically suppress pancreatic ductal adenocarcinoma proliferation. PMID: 29489864

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      1. Thanks Ovidiu!

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         1. @Daniel: there’s more, but first I have some comments (I should have dug deeper):
            – in PDAC patients with EGFR mutation, adding an EGFR inhibitor like Erlotinib improves response, but not as much as expected; the probable reason is the inhibition of the human Equilibrative Nucleoside Transporter 1 by Erlotinib, which transporter is needed for Gemcitabine uptake; a possible solution, besides administering Gemcitabine before Erlotinib, could be Astaxanthin (available as a supplement), which is able to resensitize Gemcitabine-resistant human pancreatic cancer cells to Gemcitabine, by upregulating hENT1 and downregulating ribonucleoside diphosphate reductase (RRM) 1 and 2;
            Erlotinib, gefitinib, and vandetanib inhibit human nucleoside transporters and protect cancer cells from gemcitabine cytotoxicity. PMID: 24170548
            Astaxanthin inhibits gemcitabine-resistant human pancreatic cancer progression through EMT inhibition and gemcitabine resensitization. PMID: 29098031
            – before trying the RON antibody MMAE conjugate against PDAC lines and in mouse model, the same team tried a RON antibody conjugated with a maytansinoid, which achieved good results against other cancers, but against PDAC the results were variable between cell lines; it seems the potency of MMAE is needed to kill pancreatic CSCs;
            – Avasimibe is not new, it was proposed for atherosclerosis, but failed human trials and was not developed; maybe it could be repurposed, if it will prove useful against other cancers too (prostate cancer bone metastases contain a high level of cholesterol), or as an anti-viral against hepatitis C;

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   3. Since about 80% of PDAC cell lines have the Kras mutation, and this increases the sensitivity to ferroptosis, compared to Kras-wildtype, regimens containing ferroptosis inducing agents could help, while avoiding ferroptosis inhibitors. Ferroptosis inducers are Erastin, Lanperisone (a muscle relaxant), Sorafenib, Sulfasalazine, anti-malarials Artemisinin, Artesunate, Artemether, and various new compounds. Artesunate is able to induce ferroptosis in PDAC cell lines, but not much without iron-saturated holo-transferrin, and HTF also potentiated Erastin (which disappointed in clinical trials, probably because of low uptake by cancer cells), especially at lower concentrations. Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells. PMID: 26097885
      The sigma receptors 1 and 2 have complicated functions, that are used by ligands (agonists or antagonists) to achieve a pharmacological purpose. Examples of sigma ligands are: Citalopram, Fluoxetine, Ketamine, Noscapine, Haloperidol and Sertraline. Sigma 1 antagonists and sigma 2 agonists have anti-cancer properties. Interesting, Haloperidol (which also inhibits PDAC by inhibiting DRD2 ) is also a ferroptosis inducer, and synergizes with Erastin and Sorafenib. Haloperidol, a sigma receptor 1 antagonist, promotes ferroptosis in hepatocellular carcinoma cells. PMID: 28756230
      Sigma 2 receptor was recently proposed as a promising target for pancreatic cancer therapy, by ligands conjugated to toxic payloads.
      Conjugating a sigma 2 ligand with a SMAC mimetic, SW IV-134 was born, which strongly synergizes with Gemcitabine against PDAC. The Targeted SMAC Mimetic SW IV-134 is a strong enhancer of standard chemotherapy in pancreatic cancer. PMID: 28095907
      Quoting: The Erastin derivative des-methyl Erastin (dm-Erastin, easier to synthesize and with similar potency) was chemically linked to sigma-2 ligand SV119 to create SW V-49. Conjugation increased the killing capacity of dm-Erastin by nearly 35-fold in vitro and
      reduced the size of established tumors and doubled the median survival in syngeneic and patient-derived xenograft models when compared to non-targeted dm-Erastin. Mechanistic analyses demonstrated that cell death was associated with robust reactive oxygen species production and could be efficiently antagonized with antioxidants.
      Conjugation to the sigma-2 ligand SV119 overcomes uptake blockade and converts dm-Erastin into a potent pancreatic cancer therapeutic. PMID: 27244881
      I wonder if the combination of SW V-49 with Haloperidol could do even better…

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   4. The central regions of PDAC tumors are hypoxic and necrotic, infiltrated by immunosuppressive cells. Gemcitabine and nab-Paclitaxel are much less effective under such conditions. Addition of a hypoxia-activated prodrug, Evofosfamide (TH-302), to the GnP regimen, greatly improved the response rate, with minimal extra toxicity (compared with GnP). Evofosfamide also proved synergetic with radiotherapy.
      Efficacy and safety of the hypoxia-activated prodrug TH-302 in combination with gemcitabine and nab-paclitaxel in human tumor xenograft models of pancreatic cancer. PMID: 25679067
      A Combination of Radiation and the Hypoxia-Activated Prodrug Evofosfamide (TH-302) is Efficacious against a Human Orthotopic Pancreatic Tumor Model. PMID: 28778024

      Previously, attenuated Listeria was linked to Re-188 labeled antibodies, and then injected to mice bearing PDAC xenografts, resulting in reduction of the primary tumor by more than 60%, and the number of detectable metastases was reduced by more than 90%.
      However, this method is difficult to reproduce at a large scale, so a simpler method was devised. Instead of coupling Re-188 to Listeria with help of anti-Listeria antibodies, they incorporated 32-Phosphorus (32P) directly into the Listeria by using 32P as a nutrient in the culture medium, without the need of antibodies. The results were impressive, most likely because of the longer half-life of 32P (14 days) compared to Re-188 (16.9 hrs). At the end of the treatments (day 28), primary tumors were undetectable by eye in 100% of the mice, and just a few metastases were detected in 20% of the mice that received Listeria-32P. 43% of the mice that received Listeria-32P were free of cancer, and the other 57% of the mice treated with Listeria-32P lived twice as long as controls.
      I believe the addition of a radio-sensitizer (maybe Evofosfamide, but I don’t know how it interacts with Listeria) could further improve survival, since a large percentage of the damage to the cancer cells was done by radiation, and hypoxic (damaging to radiotherapy) conditions in the central regions of the tumors may have decreased the efficacy of 32P.
      32-Phosphorus selectively delivered by listeria to pancreatic cancer demonstrates a strong therapeutic effect. PMID: 28186976

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4. Regarding Disulfiram, I am adding some recent information on the large discrepancy between the in vitro and in vivo efficacy. Quoting from article:

   The high and selective anticancer activity of DS in the laboratory has been known for more than three decades but no promising clinic data were published. We hypothesized that the discrepancy between laboratory and clinic was introduced by the metabolism of DS in cancer patients. The anticancer activity is dependent on ROS generated from the reaction between DS and copper and the final product, Cu-DDC. When orally administered, DS is enriched in liver and promptly metabolized to S-methyl and S-glucuronide DDC. The S-methylation and glucuronidation block the chelation of DS with copper and compromise its anticancer activity although the antialcoholism function remained.
   The nano-encapsulation protects the thiol groups in DS and extends its half-life in the serum from less than 2 min to over 7 h and successfully
   delivers the intact DS to cancer tissues…In combination with copper, the nano-encapsulated DS has demonstrated very strong anticancer efficacy in mouse models…
   Investigation of the key chemical structures involved in the anticancer activity of disulfiram in A549 non-small cell lung cancer cell line. PMID: 30031402

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5. I missed Honokiol in the original article, so I have to mention it now: Honokiol arrests cell cycle, induces apoptosis, and potentiates the cytotoxic effect of gemcitabine in human pancreatic cancer cells. PMID: 21720559
   Also, Ciclopirox olamine, which is used against skin cancer, might be useful in pancreatic cancer: Superior efficacy of the antifungal agent ciclopirox olamine over gemcitabine in pancreatic cancer models. PMID: 29535812

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6. I also missed intravenous ascorbate, so I’ll post now about it. Quoting from one article below, some info that I find worth remembering:
   “…Previous studies have demonstrated that activation of HIF-1α is necessary for P-AscH− sensitivity. We hypothesized that pancreatic cancer (PDAC) progression and metastasis could be be targeted by P-AscH− via H2O2-mediated inhibition of HIF-1α stabilization…”
   “…Low levels of hydrogen peroxide (H2O2) stimulate HIF-1α protein accumulation while high levels inhibit HIF-1α accumulation…”
   “…When ascorbate is infused intravenously the resulting pharmacologic concentration distributes rapidly into the extracellular water space, generating ascorbate radical and H2O2 [18]. P-AscH− administered intravenously is proposed to serve as a pro-drug for delivery of H2O2 preferentially to tumor cells. Recently, Tian and colleagues demonstrated that activation of HIF triggers a Warburg effect that renders cancer cells more sensitive to P-AscH−. In their study, down regulation of HIF-1α induced resistance to P-AscH−, while overexpression of constitutively active HIF subunits enhanced P-AscH− toxicity…”
   Pharmacologic ascorbate (P-AscH−) suppresses hypoxia-inducible Factor-1α (HIF-1α) in pancreatic adenocarcinoma. PMID: 29396728
   Tumor cells have decreased ability to metabolize H2O2: Implications for pharmacological ascorbate in cancer therapy. PMID: 27833040
   Treatment of pancreatic cancer with intravenous vitamin C: a case report. PMID: 29438178

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7. Dear all,
   Below is a link to some report that might give additional hope. Let’s hope it will be successful and quick!

   The report in an Israeli newspaper – “PJ34, a stroke therapy, is seen to offer ‘great potential’ for causing the aggressive tumor, as well as others, to self-destruct in humans..”
   https://www.timesofisrael.com/in-possible-breakthrough-molecule-destroys-pancreatic-cancer-cells-in-mice/

   And in Oncotarget:
   http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=27268&path%5B%5D=87898

   Also, in an interview in Israely TV channel 11, Prof’ Malka Cohen-Armon, from the Tel-Aviv University, said that in parallel to phase1 clinical trial that expected to take 1-2 years they might approach the FDA to approve this treatment as compation treatment.

   Best regards,
   Nissim

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   1. Dear Nissim,

      Thanks a lot for sharing this very nice result of the Israeli research team. I understand that PJ34 is a PARP1 inhibitor. PARP1 inhibitors are available in the market, such as that of Clovis Oncology (Rubraca) or other small and large pharma companies. However, I understand that the mechanism identified by the team here is a different one (prevents the clustering of NuMA in the mitotic spindle poles of human cancer cells) compared to that related to the PARP inhibition, and that comes at a higher dose of PJ34 vs the dose required to inhibit PARP. Given this high dose, my question would be what are the expected side effects. But I understand that there is a good chance the side effects are manageable: “According to the present results, PJ34 does not seem to harm the well being of the treated mice, or their weight gain”.

      Thanks again. Very interesting!

      Kind regards,
      Daniel

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