Enhanced targeted therapy for colorectal cancer - colorectal cancer (CRC) is the second leading cause of cancer-related deaths

The National Cancer Institute awarded Health Research, Inc. (Roswell Park Division), doing business as Health Research At Roswell Park, $446,112 on September 1, 2026, under the Cancer Treatment Research program (CFDA 93.395) to conduct enhanced targeted therapy research for colorectal cancer.

The research tests the synergistic potential of combining MAPK kinase cascade inhibitors with ribavirin, a GTP synthesis inhibitor, against BRAF- and RAS-mutated colorectal cancer. Work includes testing this drug combination in patient-derived xenografts and in immunocompetent mouse models of metastatic colorectal cancer to evaluate whether the combination can be effectively paired with immune checkpoint inhibitors. The research addresses a significant clinical gap: while MAPK kinase pathway targeting has shown benefit in other cancers, colorectal cancer lacks satisfactory management options when diagnosed at metastatic or regionally advanced stages, and both traditional chemotherapy and immunotherapy have limited efficacy in most patients.

Performance occurs in Buffalo, New York, with an award period from September 1, 2026, through August 31, 2028. This is a Project Grant, an assistance type supporting hypothesis-driven basic and translational research.

While early-stage diagnosis of this disease offers excellent chances of cure, the disease is often diagnosed after regional or distal spread, with much worse outcomes. The metastatic form of colorectal cancer still lacks satisfactory management options: traditional chemotherapy fails to achieve objective responses in most patients, and immunotherapy is inapplicable in most cases. A large subset of CRC is driven by mutations in braf and RAS-family oncogenes, which activate oncogenic mapk kinase cascade. Targeting the enzymes of this biochemical pathway emerged as a valuable treatment option in other cancers, but is yet to show a comparable benefit in CRC. Prior work of US and others has established an additional pathway that modulates the intensity of the mapk kinase cascade and may provide resistance to the targeted therapies. The recently uncovered hyper-dependence of that pathway on DE novo GTP biosynthesis offers an opportunity to enhance the available targeted therapies by combining them with inhibitors of GTP production. In our preliminary studies, we saw significant synergy in vitro and in vivo between the two classes of drugs against braf- and RAS-mutated CRC-derived cell lines. Following on these observations, we will test the ability of ribavirin, a common anti-viral agent and a GTP synthesis inhibitor, to synergize with mapk kinase cascade inhibitors in suppressing the growth of patient-derived xenografts, which are a more representative model of human disease. Moreover, considering the beneficial and sometimes curative effects of immune therapy in other malignancies, we will elucidate whether the new drug combination could also be effectively combined with inhibitors of immune checkpoints. This will be tested in a model of a metastatic CRC in immunocompetent mice. The treatment-induced changes in the status of various tumorassociated immunocytes will be explored. We will also profile and compare the transcriptional changes occurring in cancerous and normal cells within the tumor microenvironment upon treatment with single drugs or the combination thereof. This will help our understanding of the processes underlying the activity of the new drug combination and would pave the way for further increasing its efficacy and safety. Importantly, the phenomena under our investigation depend on the interaction of tumor cells and the therapeutic compounds with specific microenvironment of the liver, as well as with the immune system. These interactions cannot be accurately modeled in cultured cells, thus necessitating experiments to be performed in animals. Considering that the agents investigated in this study represent drugs already in human use for other indications, the success of this project will create an opportunity to expediently translate the findings into clinics, finally providing effective and generally applicable treatment options for this deadly disease.