Note: The name of Aminex’s combination drug changed from PaBT to AMXT 1501/DFMO in August 2015. Earlier publications use the previous name, PaBT or Polyamine-Blocking Therapy. It was changed to AMXT 1501/DFMO to be more consistent with drug-naming convention. The drug itself is unchanged.
- Publication of collaborative research highlighting the immunosuppressive role of increased polyamines and the ability of AMXT 1501/DFMO to overcome this immune suppression. “Polyamine-Blocking Therapy Reverses Immunosuppression in the Tumor Microenvironment.” Hayes, C.S.; Shicora, A.C.; Keough, M.P.; Snook, A.E.; Burns, M.R.; and Gilmour, S.K. Cancer Immunology Research, 2014, 2(3), 274–85 (see http://www.ncbi.nlm.nih.gov/pubmed/24778323).
- Publication of collaborative research results demonstrating potential for using Aminex’s AMXT 1501/DFMO for treatment of neuroblastoma. “AMXT-1501, a novel polyamine transport inhibitor, synergizes with DFMO in inhibiting neuroblastoma cell proliferation by targeting both ornithine decarboxylase and polyamine transport.” Samal, K.; Zhao, P.; Kendzicky, A.; Yco, L.P.; McClung, H.; Gerner, E.; Burns, M.; Bachmann, A.S.; and Sholler, G. Int. J. Cancer, 2013, 133(6), 1323–33 (see http://www.ncbi.nlm.nih.gov/pubmed/23457004).
- Publication of collaborative research confirming in predictive animal studies that AMXT 1501/DFMO has strong potential to be a major therapy for neuroblastoma, an early childhood nerve cancer with high mortality rates. “Polyamine pathway inhibition as a novel therapeutic approach to treating neuroblastoma.” Gamble, L.; Hogarty, M.; Liu, X.; Ziegler, D.; Marshall, G.; Norris, M.; and Haber, M. Frontiers in Oncology: Cancer Molecular Targets and Therapeutics, 2012, 2 (11), 162, 1-10 (see http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499881/pdf/fonc-02-00162.pdf).
- Results from phase I/II trial using AMXT 1501/DFMO for oral cancers in house cats has been published. “Phase I/II clinical trial of 2-difluoromethylornithine (DFMO) and a novel polyamine transport inhibitor for feline oral squamous cell carcinoma.” . Skorupski, K.A.; O’Brien, T.G.; Guerrero, T.; Rodriguez, C.O., and Burns, M.R. Vet Comp Oncol. 2011, 9(4), 275–82 (see http://www.ncbi.nlm.nih.gov/pubmed/22077408).
- A December 15, 2015 article in The Journal of Immunology, titled “Targeting Ornithine Decarboxylase by α-Difluoromethylornithine Inhibits Tumor Growth by Impairing Myeloid-Derived Suppressor Cells,” is an excellent article regarding another organization’s testing of one of the two drug components comprising Aminex’s lead drug, AMX-513 (now AMXT 1501/DFMO). The “α-Difluoromethylornithine” (DFMO) in this article’s title is the component of Aminex’s drug which is discussed.This article indicates their DFMO animal study findings are consistent with prior findings in similar Aminex studies which demonstrated DFMO’s ability to impair the immune suppressive function of myeloid-derived suppressor cells (MDSCs). Aminex studies show ornithine decarboxylase (ODC) inhibition by DFMO exerts an indirect immune-mediated, antitumor effect through inhibition of MDSC-mediated immunosuppressive mechanisms. Aminex has shown greater anti-tumor effects when DFMO is combined with its patented drug candidate, AMXT-1501.As discussed in the Science section of this Aminex web site, the second component of Aminex’s drug is AMXT-1501. This drug performs supporting and complementary functions to DFMO by reducing the cancers ability to replace polyamines, depleted by DFMO. This is achieved by reducing the transport of additional polyamines through the bloodstream and into cancer cells.AMXT-1501 was designed by Dr. Mark Burns, Aminex’s President and Chief Scientific Officer, to compensate for DFMO’s deficiency which was not contemplated some 30 years ago in human clinical trials for cancer. DFMO did what it was designed to do in depleting cancer cell production of polyamines, which reduced cancers’ progression for the short term. However, DFMO could not overcome cancer’s ability to replace polyamines by the transport of additional polyamines through the bloodstream. DFMO alone was unable to achieve sufficient efficacy to receive FDA approval as a cancer treatment. The earlier work of Dr. Burns’ is referenced in the article linked below.Aminex has developed the combination drug, AMXT-1501/DFMO, comprised of DFMO and AMXT 1501. Perhaps one of Aminex’s most profound discoveries is that reducing polyamines in cancer cells and MDSCs in the cancer micro-environment results in an indirect, immune-mediated, antitumor effect which can be transformational in cancer treatment by allowing immune cells to attack cancer cells.
Aminex’s vision is for this combination to achieve the original goals of DFMO to reduce tumor growth and, further, to exert an indirect immune-mediated antitumor effect that can attack and clear the tumor using natural immune functions. Aminex’s AMXT-1501/DFMO dual drug therapy is expected to be effective alone or in combination with select immunotherapy drugs already approved or in development.
Link: The abstract and access to the full article can be found at: http://www.jimmunol.org/content/early/2015/12/08/jimmunol.1500729.abstract
- Below is an abstract of a science paper, The mechanisms by which polyamines accelerate tumor spread by Kuniyasu Soda., published in the Journal of Experimental & Clinical Cancer Research. This paper explains the role of polyamines in cancer. Aminex’s AMXT-1501/DFMO drug is a combination of two drugs. Each of these drugs have mechanisms of action which reduce polyamines in cancer environments by blocking a cancer’s two primary sources of polyamines, 1. synthesis (production) in cancer cells and, 2. transport (receiving polyamines from the blood stream). This polyamine reduction plays a significant role in AMXT-1501/DFMO’s ability to trigger the immune system’s response to attack cancer and reduce its spreading.
Increased polyamine concentrations in the blood and urine of cancer patients reflect the enhanced levels of polyamine synthesis in cancer tissues arising from increased activity of enzymes responsible for polyamine synthesis. In addition to their de novo polyamine synthesis, cells can take up polyamines from extracellular sources, such as cancer tissues, food, and intestinal microbiota. Because polyamines are indispensable for cell growth, increased polyamine availability enhances cell growth. However, the malignant potential of cancer is determined by its capability to invade to surrounding tissues and metastasize to distant organs. The mechanisms by which increased polyamine levels enhance the malignant potential of cancer cells and decrease antitumor immunity are reviewed. Cancer cells with a greater capability to synthesize polyamines are associated with increased production of proteinases, such as serine proteinase, matrix metalloproteinases, cathepsins, and plasminogen activator, which can degrade surrounding tissues. Although cancer tissues produce vascular growth factors, their deregulated growth induces hypoxia, which in turn enhances polyamine uptake by cancer cells to further augment cell migration and suppress CD44 expression. Increased polyamine uptake by immune cells also results in reduced cytokine production needed for antitumor activities and decreases expression of adhesion molecules involved in antitumor immunity, such as CD11a and CD56. Immune cells in an environment with increased polyamine levels lose antitumor immune functions, such as lymphokine-activated killer activities. Recent investigations revealed that increased polyamine availability enhances the capability of cancer cells to invade and metastasize to new tissues while diminishing immune cells’ antitumor immune functions.
Link to full article: http://link.springer.com/article/10.1186/1756-9966-30-95/fulltext.html
- This referenced article, “James Allison: The Texas T Cell Mechanic,” was published by the ‘Cancer Research Institute” in mid-2015. Dr. Allison was an early, major pioneer and current thought leader in immunotherapy, today’s dynamic growth field in cancer treatment. Allison’s work has been significantly in the immunotherapy segment called Checkpoint Blockers which is a close cousin of Aminex’s therapy.
Aminex’s unique, lead drug combination, AMXT-1501/DFMO, is a suppressor cell modulator (SCM), which is a new class within immunotherapy. AMXT-1501/DFMO regulates the population of myeloid-derived suppressor cells (MDSCs) and polyamines, both expressing mechanisms which suppress the immune system.
In this article, Dr. Allison states: “It’s compelling to think of the immune system in cancer for three reasons,” summarized here.
- The incredible specificity of the immune system to target cancer cells specifically with very few of the side effects associated with conventional drugs.
- The immune system can adapt as the tumor changes.
- You can get memory and that’s the hallmark of the immune system that doesn’t exist for any other type of cancer therapy.
Aminex’s AMXT-1501/DFMO addresses different targets than checkpoint blocker drugs, but, has demonstrated these three characteristics in numerous animal tests and multiple cancer types. We also concur with another key point of Allison’s: different drugs, used in combination, offer the opportunity for more effective therapy. Aminex’s patented drug is a combination of two drugs described in this web site and has demonstrated, in animals, enhanced effectiveness when used with certain other cancer drugs.
Link to Article: http://www.
- For those interested in a more detailed, scientific paper regarding checkpoint blockers, below is a link to a long paper, with abstract, ‘Checkpoint Blockage in Cancer Immunotherapy’ written by James Allison and two associates, published by The National Center for Biotechnology Resource PubMed Center, US National Library of Medicine, National Institutes of Health in 2007.
pmc/articles/PMC1951510/There are many such papers available as this is currently the most active area of research and development in the cancer therapy field.