Pancreatic cancer: Towards increasing treatment effectivness

Dear Visitors, below is a list of drugs recently shared with me by a reader of this website. It contains relevant information and consequently I decided to publish it as a specific article. I hope this will help:

Currently the two most effective regimens in advanced pancreatic cancer are FOLFIRINOX (folinic acid, fluorouracil, irinotecan and oxaliplatin) and GnP (gemcitabine plus nab-paclitaxel). Statistically, FOLFIRINOX appears to be the best, but has higher toxicity. Also, when coupled with radical resection of primary tumor and metastases, may even lead to long term survival. In case the tumor or metastases are not removable by conventional surgery, an ablation technique like radiofrequency, cryo, laser or high intensity focused ultrasound can be used instead. However, the cancer cells that survive the ablation, either in distant micrometastases or in peritumoral tissue, are going to increase their stemness and chemoresistance. In the following I’ll try to present options that may increase the effectiveness of the GnP regimen, based on published research.

TL-118 anti-angiogenic regimen, added to Gemcitabine, is a combination of 4 drugs that target nonoverlapping aspects of the angiogenic process. The 4 drugs are cimetidine, metronomic cyclophosphamide, diclofenac and sulfasalazine. TL-118—anti-angiogenic treatment in pancreatic cancer: a case report http://www.ncbi.nlm.nih.gov/pubmed/23609193 The regimen resulted in near complete response, but was poorly tolerated and interrupted. For a comprehensive list of cimetidine applications on cancer, Repurposing drugs in oncology (ReDO) – cimetidine as an anti-cancer agent. http://www.ncbi.nlm.nih.gov/pubmed/25525463

The paper includes a reference to Targeting Mitochondrial STAT3 with the Novel Phospho-Valproic Acid (MDC-1112) Inhibits Pancreatic Cancer Growth in Mice http://www.ncbi.nlm.nih.gov/pubmed/23650499

Sulfasalazine has been previously proposed as gemcitabine adjuvant, Potential use of the anti-inflammatory drug, sulfasalazine, for targeted therapy of pancreatic cancer http://www.ncbi.nlm.nih.gov/pubmed/20567622

Diclofenac, and old anti-inflammatory drug,  inhibits both VEGF and glycolysis. Diclofenac Inhibits Tumor Growth in a Murine Model of Pancreatic Cancer by Modulation of VEGF Levels and Arginase Activity http://www.ncbi.nlm.nih.gov/pubmed/20856806

New Aspects of an Old Drug – Diclofenac Targets MYC and Glucose Metabolism in Tumor Cells http://www.ncbi.nlm.nih.gov/pubmed/23874405

Curcumin has proven helpful in various cancers, but is hampered by low bioavailability. It synergizes with many chemotherapy drugs, including gemcitabine and paclitaxel. Systemic Administration of Polymeric Nanoparticle-Encapsulated Curcumin (NanoCurc) Blocks Tumor Growth and Metastases in Preclinical Models of Pancreatic Cancer. http://www.ncbi.nlm.nih.gov/pubmed/20647339 However, there are newer formulations of curcumin with better bioavailability, like Meriva (formulated with phosphatidylcholine), that proved useful in colorectal cancer. Curcumin ameliorates oxaliplatin-induced chemoresistance in HCT116 colorectal cancer cells in vitro and in vivo. http://www.ncbi.nlm.nih.gov/pubmed/20839263 Other new formulations of curcumin are Theracurmin and NovaSOL.

Tocotrienols, delta and gamma (from Annatto) also synergize with gemcitabine. Vitamin E delta-tocotrienol prolongs survival in the LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) transgenic mouse model of pancreatic cancer. http://www.ncbi.nlm.nih.gov/pubmed/23963802 A Phase I Safety, Pharmacokinetic, and Pharmacodynamic Presurgical Trial of Vitamin E delta-tocotrienol in Patients with Pancreatic Ductal Neoplasia. http://www.ncbi.nlm.nih.gov/pubmed/26844278

Evodiamine, an extract from Evodia plants. Enhanced Antitumor Efficacy of Gemcitabine by Evodiamine on Pancreatic Cancer via Regulating PI3K/Akt Pathway http://www.ncbi.nlm.nih.gov/pubmed/22211100

Disulfiram, synergizes in vitro with both gemcitabine and paclitaxel. However, disulfiram metabolites are less potent and less studied. Gemcitabine response in pancreatic adenocarcinoma cells is synergistically enhanced by dithiocarbamate derivatives http://www.ncbi.nlm.nih.gov/pubmed/21236335 Reversing the Intractable Nature of Pancreatic Cancer by Selectively Targeting ALDH-High, Therapy-Resistant Cancer Cells http://www.ncbi.nlm.nih.gov/pubmed/24194908 Disulfiram targets cancer stem-like cells and reverses resistance and cross-resistance in acquired paclitaxel-resistant triple-negative breast cancer cells http://www.ncbi.nlm.nih.gov/pubmed/24008666 There is a new liposomal formulation, Liposome encapsulated Disulfiram inhibits NF-kB pathway and targets breast cancer stem cells in vitro and in vivo http://www.ncbi.nlm.nih.gov/pubmed/25277186

A combination of dietary agents show promise against pancreatic cancer, Sulforaphane, quercetin and catechins complement each other in elimination of advanced pancreatic cancer by miR-let-7 induction and K-ras inhibition http://www.ncbi.nlm.nih.gov/pubmed/25017900

Most of the above focused on gemcitabine synergy, but to get most of nab-paclitaxel, it is possible to use lansoprazole, Lansoprazole induces sensitivity to suboptimal doses of paclitaxel in human melanoma http://www.ncbi.nlm.nih.gov/pubmed/25449440 High dose lansoprazole combined with metronomic chemotherapy: a phase I/II study in companion animals with spontaneously occurring tumors. http://www.ncbi.nlm.nih.gov/pubmed/25143012

Other potentially useful drugs or supplements: apricoxib, 3BP, clobenpropit, oseltamivir, omeprazole, but some at massive (unrealistic) doses.

Apricoxib, a novel inhibitor of COX-2, markedly improves standard therapy response in molecularly defined models of pancreatic cancer. http://www.ncbi.nlm.nih.gov/pubmed/22829202

Inhibition of glucose turnover by 3-bromopyruvate counteracts pancreatic cancer stem cell features and sensitizes cells to gemcitabine http://www.ncbi.nlm.nih.gov/pubmed/25015789 Systemic delivery of microencapsulated 3-bromopyruvate for the therapy of pancreatic  cancer. http://www.ncbi.nlm.nih.gov/pubmed/25326230

Clobenpropit enhances anti-tumor effect of gemcitabine in pancreatic cancer http://www.ncbi.nlm.nih.gov/pubmed/25024609

Therapeutic targeting of Neu1 sialidase with oseltamivir phosphate (Tamiflu) disables cancer cell survival in human pancreatic cancer with acquired chemoresistance http://www.ncbi.nlm.nih.gov/pubmed/24470763

Omeprazole Inhibits Proliferation and Modulates Autophagy in Pancreatic Cancer Cells http://www.ncbi.nlm.nih.gov/pubmed/21629657

An interesting new treatment, if it will be approved, radioactive Listeria.

The injection of 188Re-labeled antibodies bound to L. monocytogenes resulted in reduction of the primary tumor by more than 60%, and remarkably, the number of detectable metastases was reduced by more than 90%. Single-agent combinatorial cancer therapy http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3666690/

Most of the above can be applied to other cancers, and there is one more, deuterium depleted water, which is non-toxic and can synergize with chemotherapy.

Deuterium depletion results in several fold increases in the median survival time of cancer patients during oncotherapy.

Deuterium depleted water effects on survival of lung cancer patients and expression of Kras, Bcl2, and Myc genes in mouse lung. http://www.ncbi.nlm.nih.gov/pubmed/23441611

DDW at 25 ppm is marketed under Qlarivia brand, costs about 7 euros / liter.

By Ovidiu Herlea

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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4 Comments on "Pancreatic cancer: Towards increasing treatment effectivness"

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Wondering
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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.

Helga
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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… Read more »