Lead investigator: Susan Gilmour, PhD
Collaborator: Otto Phanstiel, PhD, University of Central Florida
A great need exists for cancer therapies that can eradicate immune myeloid suppressor cells that block the efficacy of cancer immunotherapeutics, such as immune checkpoint drugs. Small molecule inhibitors and transport-based poisons developed by scientists at LIMR and the University of Central Florida (UCF) address the intense interest in modalities to achieve this end.
Solid tumors have a huge appetite for polyamines, a class of nutrients made in the body but also acquired in the diet. While all cells use polyamines, tumor cells require much higher levels, and therefore must scavenge them through activation of a cell surface polyamine uptake system. by strongly activating a polyamine-uptake system. Blocking polyamines can arrest the growth and survival of tumor cells, but an effective strategy to selectively attack tumors by blocking their reliance on polyamine uptake has been elusive.
LIMR and UCF scientists who are leaders in the field have synthesized and characterized novel proprietary small molecules that act as polyamine transport inhibitors (PTIs) or polyamine-drug conjugates (transport-based poisons). These two strategies exploit the highly upregulated polyamine transport system in cancer, either by direct blockade or as a 'Trojan Horse' attack. Compounds in each class may offer potential for immediate clinical translation.
In preclinical studies, these strategies safely and effectively debulk tumors. Mechanistic studies show that the therapies work chiefly by eradicating myeloid-derived suppressor cells that mediate immunosuppression. Preclinical studies have demonstrated general anti-tumor efficacy in multiple experimental tumor systems, including melanoma, breast, ovarian, colorectal and pancreas cancers. Thus, the discovery offers general utility to safely heighten the anti-cancer efficacy of combination chemotherapy, molecular targeted therapy and immunotherapy.
PTIs attack tumors by blocking polyamine uptake by tumor cells and other cell types present in the tumor microenvironment. Strikingly, LIMR researchers have found that combination treatment with a PTI to block polyamine uptake with an FDA-approved drug that blocks polyamine synthesis (termed polyamine-based therapy, or PBT) activates a tumor-specific immune response that can eradicate tumors. Mechanistic investigations suggest that the PTI exerts its potent immune-activating effects by relieving an arginase-polyamine metabolic pathway that tumors use to suppress the immune system. As a result, poorly immunogenic metastatic tumors that are resistant to immunotherapy, such as anti-PD-1 therapy, become responsive when co-treated with PBT.
Polyamine-drug conjugates kill tumor cells by turning their voracious polyamine uptake against themselves. Specifically, these compounds include a polyamine moiety conjugated to a cytotoxic drug known to kill cancer cells. Since polyamine transporters are more active in cancer cells than normal cells, the greater uptake of the conjugate by cancer cells selectively kills them. This targeting principle has been shown to be safe and efficacious in preclinical testing at clinically relevant concentrations.
Stage of development
Preclinical therapeutic proof of concept in mice for this novel mechanism of action has been published.
Intellectual property position
- Composition of matter and use of polyamine transport inhibitors, U.S. Patent No. 9,730,902 (issued Aug 15, 2017).
- Composition of matter and use of polyamine-drug conjugates, U.S. Patent No. 9,926,260 (issued Mar 27, 2018).
- Use of PTI and DFMO as immunomodulatory therapy, patent pending.
- Collaboration agreement in place between LIMR and UCF with sharing of intellectual property.
Pharmacology and toxicology analysis of candidate lead compounds.
Hayes CS, Shicora AC, Keough MP, Snook AE, Burns MR and Gilmour SK. (2014). Polyamine-blocking therapy reverses immunosuppression in the tumor microenvironment. Cancer Immunol Res. 3:274-85.
Alexander ET, Minton A, Peters MC, Phanstiel IV O and Gilmour SK. (2017). A novel polyamine blockade therapy activates an anti-tumor immune response. Oncotarget. 8:84140-52.
Peters MC, Minton A, Phanstiel IV O and Gilmour SK. (2018). A novel polyamine-targeted therapy for BRAF mutant melanoma tumors. Med Sci. 6:3.
Institutional contact: George C. Prendergast, PhD, LIMR President and CEO, 484.476.8475, firstname.lastname@example.org
IP manager contact: Heather Rose, PhD, JD, VP of Technology Licensing and Startups, Thomas Jefferson University, 215.503.0770, email@example.com