Home Conference Coverage Fourth RAS Initiative Symposium Highlights Preclinical Data in Solid Tumor Models

Fourth RAS Initiative Symposium Highlights Preclinical Data in Solid Tumor Models

During the National Cancer Institute (NCI-) sponsored Fourth RAS Initiative Symposium held October 17-19, 2022 at The Advanced Technology Research Facility of the National Cancer Institute in Frederick, Maryland, Qualigen Therapeutics presented two posters detailing the company’s RAS-Targeted platform.

The goal of the symposium was to mobilize the cancer research community to develop ways to understand and target cancers driven by mutant RAS in an open model of collaboration among government, academic, and industry researchers.

RAS is a GTPase that is frequently mutated in cancer and that affects a variety of cancer-driving processes. It drives cellular proliferation by providing both cell-autonomous and non-cell-autonomous cues, which ultimately converge in the transformed cells to promote pro-growth and to inhibit anti-growth signals. [1]

As one of the most common cancer oncogene, RAS activates mutations in one of the three human RAS gene isoforms, including KRAS, HRAS, and NRAS, which are present in about one-fourth of all cancers.

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Tumor microenvironment
Oncogenic RAS modulates the tumor microenvironment, which includes the tumor’s surrounding blood vessels, immune cells, fibroblasts, signaling molecules and the extracellular matrix, by promoting pro-angiogenic mechanisms and by altering host-mediated immune responses. In addition, transformation by RAS can also promote changes in motility and cellular adhesion, leading to the acquisition of invasive and metastatic properties of cancer cells.

Mutant KRAS
Mutant KRAS, for example, is found in 98% of pancreatic ductal adenocarcinomas, 52% of colon cancers, and 32% of lung adenocarcinomas.

According to the National Cancer Institute, mutant KRAS subsets of these three cancers alone are diagnosed in more than 170,000 people each year in the United States, resulting in more than 120,000 deaths annually. [2] Substantial scientific and pharmaceutical industry interest is evident by the compounds either approved or in development to treat devastating RAS-driven advanced solid tumors, such as pancreatic cancer.

“RAS is a key cancer oncogene present in about one quarter of all cancers. RAS development is an active field with substantial interest from the scientific community and biopharmaceutical industry,” noted Michael Poirier, Chairman and Chief Executive Officer of Qualigen Therapeutics.

“Only one FDA-approved targeted RAS inhibitor exists today and it is specific to the KRAS G12C mutation. Thus, an unmet need to discover and develop more broadly acting RAS-targeted compounds exists,” Poirier added.

“Our RAS targeted platform aims to identify a small molecule that inhibits RAS-RAS protein interaction and acts more broadly across RAS forms to treat advanced solid tumors by blocking the ability of RAS to bind and signal through its effectors. These posters, which represent early findings in our partnership with Geoff J. Clark, Ph.D. at the University of Louisville, KY, demonstrate the potential of our approach to addressing RAS.”

Malignant peripheral nerve sheath tumors
During the symposium, researchers are presenting the results of screening to identify an initial candidate inhibitor of RAS oncoproteins for malignant peripheral nerve sheath (MPNST) tumor, a fast growing type of sarcoma, that form the sheath that covers and protects peripheral nerves. The disease exhibit a low overall 5 year survival rate of less then 40%, and there is no effective treatment or cure.

As part of this study, investigators measured in vitro and in vivo activity against these tumors. The lead candidate, designated by investigators as RAS-F suppressed RAS signaling pathways and suppressed MPNST tumor growth in animal models. [3]

Pancreatic cancer
In a second study, following screening to identify an initial candidate inhibitor against pancreatic cancer tumor growth, investigators analyzed in vitro and in vivo activity against these tumors. The lead candidate, designated RAS-F, suppressed RAS signaling pathways and pancreatic tumor cell growth in vitro.[4]

It also suppressed xenograft development of human and mouse RAS-driven pancreatic tumor cell lines and reduced the growth of pancreatic cancer patient-derived xenograft models. The study also showed that RAS-F enhanced the effects of immune checkpoint therapy in syngeneic tumor xenografts.

Reference
[1] Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D. RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer. 2011 Oct 13;11(11):761-74. doi: 10.1038/nrc3106. PMID: 21993244; PMCID: PMC3632399.
[2] Cancer Stat Facts: Common Cancer Sites. Reports on Cancer. National Cancer Institute, SEER. Online. Last accesses on October 19, 2022.
[3] Donninger H, Ferril R, Ede D, vonBaby B, Jigo R, Burlison J, Sabo M, Trent J and Clark GJ. A novel pan-RAS inhibitor for Malignant Peripheral Nerve Sheath Tumors.  Presented during the Fourth RAS Initiative Symposium held October 17-19, 2022.
[4] Donninger H, Ferril R, vonBaby B, Burlison J, Sabo M, Arshad T, Trent J and Clark GJ. A Novel RAS inhibitor for Pancreatic Cancer. Presented during the Fourth RAS Initiative Symposium held October 17-19, 2022.

Featured image: National Cancer Institute’s Advanced Technology Research Facility Frederick, Maryland. Courtesy: ©. 2020 NCI. Used with permission

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