On October 26, 2022 Promontory Therapeutics Inc., a clinical stage pharmaceutical company advancing small molecule immunotherapies in oncology, reported new non-clinical data on its lead candidate, immunogenic cell death inducer PT-112, and its effects on human prostate cancer cell mitochondria (Press release, Promontory Therapeutics, OCT 26, 2022, View Source [SID1234622439]). The poster presentation titled, "Characterization of differential metabolic phenotypes and PT-112-induced mitochondrial effects in human prostate cancer cells," is available for viewing in person beginning today from 12:00pm-8:00pm CEST at the 34th 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), taking place October 26-28 in Barcelona, Spain.
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"Our findings show that PT-112 was broadly active across a variety of human prostate cancer cell lines and induced mitochondrial stress," said Alberto Anel, PhD, Professor at University of Zaragoza/Aragón Health Research Institute, Department of Biochemistry and Molecular and Cellular Biology, who led the study. "We also found that PT-112 generated massive mitochondrial reactive oxygen species (mtROS) in sensitive cell lines, and the rapid effects on mitochondrial structure suggest the importance of this organelle in the anticancer activity of Promontory’s lead therapeutic candidate."
"Ongoing studies into PT-112’s ability to induce immunogenic cell death and cancer cell organelle stresses have been encouraging and support our elucidation of the drivers of PT-112’s validated immunogenic cancer cell death," said Promontory co-founder and Chief Operating Officer Matthew Price. "These results follow a recent U.S. patent issuance related to uses of our immunogenic small-molecule compounds within immuno-oncology. The Anel lab’s work clearly supports our understanding of PT-112’s mechanisms of action as we progress in clinical trials."
The non-clinical study of PT-112 was designed to continue the characterization of PT-112’s effects on mitochondria in a panel of human prostate cancer cell lines. Key study findings included:
Human prostate cancer cell lines exhibited differential metabolic features when compared to the healthy prostate cell line RWPE-1.
Baseline mtROS levels varied across the panel, with PT-112-sensitive cell lines often showing higher mtROS levels.
Changes in the activity of respiratory (super-)complexes were observed in response to PT-112.
In PT-112-sensitive cell lines, PT-112 induced a large increase in mitochondrial mass and mtROS, consistent with the effects of mitochondrial stress.
After brief durations of PT-112 exposure, electron microscopy revealed noteworthy changes in prostate cancer cell mitochondrial structure in response to PT-112.
PT-112 is an immunogenic small molecule currently under Phase 2 clinical development, with clinical activity against heavily pretreated solid tumors, including metastatic castration-resistant prostate cancer. Prior work has shown that PT-112 causes mitochondrial stress, may be selective to cancer cells with mitochondrial defects, and promotes robust ICD.
For more information about Promontory’s clinical trials, visit the website at www.PromontoryTx.com.
About PT-112
PT-112 is the first small-molecule conjugate of pyrophosphate in oncology, and 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 a highly potent inducer of this immunological form of cancer cell death. Further, PT-112 harbors a property known as osteotropism, or the propensity of the drug to reach its highest concentrations in certain areas of the bone, making it a candidate for treatment of patients with cancers that originate in, or metastasize to, the bone. 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 combination Phase 1b dose escalation study of PT-112 with PD-L1 checkpoint inhibitor avelumab in solid tumors was reported in an oral presentation at the ESMO (Free ESMO Whitepaper) 2020 Virtual Congress. The Phase 1 study in patients with relapsed or refractory multiple myeloma presented at ASH (Free ASH Whitepaper) is the third completed Phase 1 study of PT-112. Monotherapy Phase 2 development is ongoing in mCRPC, and now includes the Phase 2 proof of concept study in thymic epithelial tumors under the company’s formal collaboration with the NCI. The PD-L1 combination Phase 2a study is ongoing in a dose confirmation cohort of non-small cell lung cancer (NSCLC) patients.