PHILADELPHIA (August 8, 2023) — A new study led by Igor Astsaturov, MD, PhD, Co-Director of the Marvin & Concetta Greenberg Pancreatic Cancer Institute at Fox Chase Cancer Center, demonstrates two key components necessary for a new drug candidate, LP-184, to effectively treat pancreatic adenocarcinoma. The findings were published today in Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research.
Pancreatic adenocarcinoma is the second most common gastrointestinal cancer in the United States. It generally has a poor prognosis because it spreads quickly.
The research is part of a two-year collaboration between his lab and Lantern Pharma, said Astsaturov, who is also an Associate Professor in the Department of Hematology/Oncology at Fox Chase. Lantern is developing LP-184, a next generation acylfulvene-class therapeutic that acts as a tumor-site activated small molecule pro-drug. It is synthetically lethal in a broad spectrum of DNA damage repair (DDR)-deficient solid tumors.
Lantern Pharma is an artificial intelligence-driven company developing targeted cancer therapies and is launching a first-in-human phase 1A clinical trial of LP-184 as a single agent in advanced solid tumors.
“Lantern wanted to know what cancer types and genomically defined patient subsets would most likely benefit from the drug. That’s where we started collaborating,” said Astsaturov. This work has involved a number of colleagues from Fox Chase and researchers from Lantern Pharma.
He said that because researchers believe the molecule causes direct DNA damage, including double strand breaks, they began focusing their efforts on studying the activity of the drug in models that carried mutations in commonly altered components in the DDR pathway.
This work showed that the pathway was a critical component of the drug’s ability to provide tumor-selective efficacy because the activated molecule binds the DNA covalently, making cancers that are unable to repair DNA properly particularly vulnerable to LP-184.
This mechanism, called synthetic lethality, refers to a situation in which mutations in two genes together result in cell death but a mutation in either gene on its own does not.
Additionally, researchers found that LP-184 is a pro-drug that needs to be activated inside the cancer cells by a specific enzyme called prostaglandin reductase (PTGR1) that is often elevated in solid tumors but not in normal tissues.
“As part of this study, PTGR1 was genetically engineered in cell lines to either be present or absent, and the study showed that when cells lose PTGR1 they lose sensitivity to the drug,” said Astsaturov. “Based on our findings, we anticipate that LP-184 will expand therapy options to a large subset of patients with genetically defined pancreatic adenocarcinoma.”
Astsaturov said following this study and the recent investigational new drug clearance of LP-184 by the Food and Drug Administration, Fox Chase will soon launch a phase 1 clinical trial for LP-184 that will evaluate its safety and preliminary efficacy profile, as well as how the body responds to it.