Expanding CR&T's Impact

Since 1968, CR&T is proud to have maintained our mission to fund research emphasizing the cause, prevention, treatment and cure of myeloproliferative neoplasms (MPN) and also fund other blood and solid tumor cancer research. While we continue our emphasis on MPNS, in 2024, we have increased our funding for solid tumor cancer research to demonstrate our dedication to tackling a wider range of cancer types. This year, a major initiative includes a grant awarded to Despina Siolas, MD, PhD, from Weill Cornell Medicine which will fund her project on "Investigating the immunogenicity of mutant Kras in pancreatic cancer", with a goal of understanding how a tumor's DNA makeup can profoundly shape the number and types of immune cells surrounding the tumor.

Project Summary

Project Title: Investigating the immunogenicity of mutant Kras in pancreatic cancer

Focus Area Addressed by Project: Pancreatic cancer causes and treatment of solid tumor cancers

Lay Project Abstract: Pancreatic cancer is a deadly disease with few treatment options. Immunotherapy is an exciting new cancer therapy, but it has limited efficacy in pancreatic ductal adenocarcinoma (PDA). Understanding why PDA tumors are resistant to immunotherapy will increase sensitivity to current treatment, improving patient outcomes.

Tumors are not simply cancer cells, but consist of other cell types, including immune cells. A tumor's DNA makeup can profoundly influence the number and types of immune cells surrounding the tumor, but the specific mutations directing immune response and their associated biochemical mechanisms are poorly understood. KRAS gene mutations are present in almost all pancreatic tumors, though there is considerable variation in patient outcomes depending on KRAS genotype. Patients with KRASG12D mutations (representing 40% of PDA cases) have poorer prognoses compared to those with KRASG12R mutations (comprising 20% of PDA cases) suggesting that KRAS mutation status affects disease behavior.

Our poor understanding of the different KRAS mutations limits our ability to design and implement appropriate treatments. The goal of this proposal is to identify immune cells within KrasG12R PDA tumors and decipher its underlying biochemical mechanism. Our preliminary data from patient samples and mouse models reveal KRASG12R mutant tumors have a distinct immune cell population consisting of CD4+ T cells and activated dendritic cells in comparison to KRASCG12D mutant tumors. The presence of dendritic cells, CD4+ T cells, and KRASG12R genotype are each linked independently to prolonged survival in PDA patients, the specific immune effects directly attributable to the KRASG12R mutation in PDA remain undefined.

We will define the role of specific types of dendritic cell and CD4+ T cells and their cytokine mediators in driving KRASG12R tumor growth using both mouse models and human tumor samples. In addition, we will identify biochemical signaling differences between KRASG12R and KRASG12D mutant tumors that attract tumor immunity. Ultimately, we aim to develop tailored and effective therapeutic strategies for patients with PDA.

You can listen to Dr. Siolas speak about Diagnosing and Treating Pancreatic Cancer with Dr. Leonard on his podcast. CancerCast wherever you listen to podcasts or at https://bit.ly/3yu94rg

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