Promontory Therapeutics Inc. presented data demonstrating the molecular mechanism of its lead therapeutic candidate, PT-112, and its ability to induce immunogenic cell death in cancer cells.
- PT-112's mechanism of action inhibits ribosomal biogenesis, promoting immunogenic cancer cell death through cancer cell organelle stresses
- Data presented at the Society for Immunotherapy of Cancer's 38th Annual Meeting
NEW YORK, Nov. 4, 2023 /PRNewswire/ -- Promontory Therapeutics Inc., a Phase 2 stage biotech company advancing immunogenic small molecule approaches in oncology, today presented data demonstrating the molecular mechanism of its lead therapeutic candidate, PT-112, and its ability to induce immunogenic cell death (ICD) in cancer cells. Data suggest that PT-112-induced ICD is mediated by endoplasmic reticulum (ER) and mitochondrial stresses, which are specific intra-cellular events that comprise part of the larger ICD mechanism. The presentation was made at the Society for Immunotherapy of Cancer's (SITC) 38th Annual Meeting, taking place November 1-5, 2023 in San Diego.
The work was designed in collaboration with the Galluzzi Lab at Weill Cornell Medical College in New York, in order to elucidate the sequence of events – beginning with inhibition of ribosomal biogenesis and culminating in selective ICD – underlying PT-112's immune effects. Analyzing a panel of mouse cell lines engineered to lack specific genes involved in mitochondrial apoptosis (Bcl2, Bax and Bak1), flow cytometry, immunoblotting, RT-PCR, and immunofluorescence microscopy were used to determine the impact of PT-112 on ER and mitochondrial stress, as well as immunogenic signaling.
"Our continued studies of PT-112 provide mechanistic insights for this promising immunogenic small molecule, which has shown clinical activity in patients with a variety of cancers," said Promontory Therapeutics Senior Vice President of Research and Development Tyler Ames, PhD. "This particular work sheds light on how PT-112 encourages the immunogenic cell death of cancerous cells through ER stress and mitochondrial dysfunction, both of which are known to contribute to immune signaling."
Study findings include:
- PT-112 drives ER stress and mitochondrial dysfunction, which promote ICD.
- PT-112 effects on mitochondria included increases in mitochondrial mass and reactive oxygen species, changes in membrane polarization, and the release of mitochondrial DNA into the cytosol, a potent immunogenic signal. Some of these effects were impacted by the absence of Bax and Bak1.
- PT-112 elicits the phosphorylation of eukaryotic translation initiation factor 2 subunit alpha (EIF2S1, best known as eIF2α), indicating ER stress and the activation of the integrated stress response (ISR).
- There is an increase in the levels of Ifnb1 mRNA after PT-112 exposure, indicating PT-112 induces type 1 interferon responses.
PT-112 is the subject of ongoing Phase 2 clinical trials for metastatic castrate-resistant prostate cancer and thymic epithelial tumors, and a completed Phase 2a trial in non-small cell lung cancer. In previous mechanism of action research, data showed that PT-112 causes ribosomal biogenesis inhibition and nucleolar stress, which is the likely driver of PT-112-induced cancer organelle stresses and ICD.
For more information about Promontory Therapeutics and PT-112, visit www.PromontoryTx.com.
About PT-112
PT-112 is a novel inhibitor of ribosomal biogenesis, which leads to selective immunogenic cancer cell death (ICD). PT-112's mechanism of action governs intracellular events that cause the release of damage associated molecular patterns, known to bind to dendritic cell and natural killer cell receptors, prompting an anti-cancer immune response. PT-112's potential best-in-class ICD effects may create the conditions for effective and durable responses to treatment. 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 data were published in eClinicalMedicine, part of The Lancet. The company's Phase 2 study of PT-112 in late-stage metastatic castration-resistant prostate cancer patients is underway in the United States and France. An active Phase 2 trial is also on-going with the National Cancer Institute utilizing PT-112 in thymic epithelial tumors, a rare disease with no FDA approved drug, for which PT-112 has received FDA Orphan Drug designation. An additional Phase 2a study has been successfully completed for non-small cell lung cancer in combination with PD-L1 inhibition.
About Promontory Therapeutics
Promontory Therapeutics Inc. is a privately held, clinical stage drug development company focused on small molecule immunotherapy in cancer. The company's lead therapeutic candidate PT-112 has demonstrated single-agent and combination anti-cancer activity and an attractive tolerability profile across three Phase 1 studies. PT-112 is the subject of ongoing Phase 2 clinical trials for metastatic castration-resistant prostate cancer in the United States and France, thymic epithelial tumors with the National Cancer Institute, and a completed Phase 2a trial in non-small cell lung cancer. As part of its recent research and development expansion into France, Promontory was selected as the first international company member of the Paris-Saclay Cancer Cluster, Europe's emerging biotech hub for oncology.
To learn more about Promontory Therapeutics, visit the company's website here.
CONTACTS:
Promontory Therapeutics:
Brooke Raphael, MS
VP, Strategy & Operations
Tel: +1 (646) 974-6453
Email: braphael@promontorytx.com
Investors:
Stan Musial
Chief Financial Officer
Tel: +1 (646) 222-6932
Email: smusial@promontorytx.com
Media:
Alexis Feinberg
ICR Westwicke
Tel: +1 (203) 939-2225
Email: alexis.feinberg@westwicke.com
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SOURCE Promontory Therapeutics Inc.
