On October 27, 2020 Phosplatin Therapeutics LLC, a clinical-stage pharmaceutical company focused on oncology therapeutics, presented new data showing that glycolytic tumor cells with mitochondrial dysfunction were more sensitive to cell death induced by PT-112, the company’s lead clinical agent, compared to cells with an intact oxidative phosphorylation pathway (Press release, Phosplatin, OCT 27, 2020, View Source [SID1234569110]). The type of cell death induced by PT-112 was also shown to involve autophagy, which is a known pre-cursor of immunogenic cell death (ICD). Such findings reinforce PT-112’s divergence from the canonical expectations surrounding cell death mechanisms of platinum-containing agents. Data were presented at the 32nd Symposium of the European Organisation for Research and Treatment of Cancer (EORTC), the National Cancer Institute (NCI) and the American Association for Cancer Research (AACR) (Free AACR Whitepaper), which took place virtually October 24-25.
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"PT-112’s selectivity to glycolysis-dependent cells over those able to conduct aerobic respiration, and its initiation of autophagy, are promising mechanistic findings that tie in well with PT-112’s ability to induce ICD. These findings may offer opportunity for subsequent clinical applications," said Tyler Ames, PhD, SVP of Research and Development, Phosplatin Therapeutics.
Led by Professor Alberto Anel, PhD of the University of Zaragoza Aragón Health Research Institute of Zaragoza, Spain, the study used the lab’s proprietary cellular models to demonstrate high sensitivity to PT-112 exposure of glycolysis-dependent cancerous cells harboring mitochondrial DNA mutations and high expression of HIF-1a, and a degree of selectivity not observed with cisplatin control. The study authors attributed the variance in response to differences in cellular targets and/or reactive oxygen species (ROS) generation by PT-112. Initial validation of these data in human cancer cells is ongoing. ROS generation is also known from the literature as a pre-cursor to ICD.
"As we continue to learn more about PT-112 and its unique set of cellular effects, we gain greater insight into its pleiotropic mechanism of action, the possible causes of its robust ICD induction, and its breadth of potential clinical application," said Matthew Price, co-founder and Chief Operating Officer, Phosplatin Therapeutics. "We are grateful for our collaboration with the Anel lab. Our hope is that such collaborative lab research, as well as our ongoing clinical correlative studies, will further illuminate ways in which we can continue successfully to treat cancer patients who have few available treatment options."
The abstract "PT-112, A First-In-Class Pyrophosphate-Platinum Conjugate, Selectively Targets Highly Glycolytic Tumor Cells" is available along with a narrated poster presentation at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) symposium site and on the Phosplatin Therapeutics website.
About PT-112
PT-112 is a novel small molecule conjugate of pyrophosphate that possesses a unique pleiotropic mechanism of action that promotes immunogenic cell death (ICD), through the release of damage associated molecular patterns (DAMPs) that bind to dendritic cells and lead to downstream immune effector cell recruitment in the tumor microenvironment. PT-112 represents the best-in-class small molecule inducer of this immunological form of cancer cell death and is currently under Phase II development. The first in-human study of PT-112 demonstrated an attractive safety profile and evidence of long-lasting responses among heavily pre-treated patients and won "Best Poster" within the Developmental Therapeutics category at the ESMO (Free ESMO Whitepaper) 2018 Annual Congress. The novelty of PT-112’s pyrophosphate moiety also results in osteotropism, or the propensity of the drug to reach the mineralized bone. This property is of interest in cancer types that originate in or metastasize to the bone. The combination Phase Ib study of PT-112 with PD-L1 immune checkpoint inhibitor avelumab in solid tumors was reported in an oral presentation at the ESMO (Free ESMO Whitepaper) 2020 Virtual Congress.