Publications

Publications

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 research led by Childrens Cancer Institute and Sydney Children’s Hospital detailing findings of DFMO and AMXT 1501 in animal studies of DIPG. “Dual targeting of polyamine synthesis and uptake in diffuse intrinsic pontine gliomas.” Nature Communications, 12 February 2021. 12, Article number: 971 (2021). (see https://www.nature.com/articles/s41467-021-20896-z)
• Publication of international, collaborative research findings identifying MYCN gene responsible for uptake of polyamines by neuroblastoma cells and inhibition of this gene using AMXT-1501. “Inhibition of polyamine synthesis and uptake reduces tumor progression and prolongs survival in mouse models of neuroblastoma.” Science Translational Medicine, 30 Jan. 2019, Vol. 11, issue 477. (see https://tinyurl.com/yys7d2zc )
• 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).

Articles

• 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

Abstract

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