Memorial Sloan Kettering Cancer Center (MSK) experts presented findings from their latest foundational and translational cancer research at the American Association for Cancer Research (AACR) Annual Meeting 2024, held April 5 to 10 in San Diego.
Highlights included discoveries of mechanisms driving cancer mutational processes in solid tumors, such as colorectal cancer and ovarian cancer. Additional topics included the development of a new type of chimeric antigen receptor (CAR) T cells for targeting a broad range of solid tumors and assessing minimal residual disease in solid tumors with high-value clinical applications.
Each summary below demonstrates the breadth of multidisciplinary collaboration at MSK to investigate the most pressing questions in cancer research.
Dissecting Plasticity During Colorectal Cancer Progression
Physician-scientist Karuna Ganesh, MD, PhD, a medical oncologist specializing in gastrointestinal oncology, was an invited speaker for the AACR-Bayard D. Clarkson Symposium: Cellular Plasticity in Tumor Development, Metastasis, and Response to Therapy. She presented findings on plasticity during colorectal cancer progression.
Dr. Ganesh and colleagues, including co-senior author Dana Pe’er, PhD, Chair of the Computational and Systems Biology Program at MSK’s Sloan Kettering Institute, examined biospecimen trios from same-patient normal colon, primary and metastatic colorectal cancer prospectively collected from 31 patients who underwent synchronous colorectal tumor resection and metastasectomy at MSK between February 2019 and September 2021. All patients had microsatellite stable, mismatch-repair proficient metastatic colorectal cancer. Nine patients received no treatment before surgery, and 22 received neoadjuvant 5-fluoroacil-based chemotherapy.
The investigators discovered that primary tumors largely adopted intestinal stem-like states, yet metastases with non-canonical gene expression demonstrated progressive plasticity, a loss of intestinal stem-like states, and were reprogrammed in two sequential steps despite tumoral heterogeneity across patients — a highly-conserved fetal progenitor state, followed by non-canonical differentiation into divergent squamous and neuroendocrine-like states. These processes were exacerbated and associated with poorer clinical outcomes among patients who received neoadjuvant chemotherapy compared to patients who did not.
Dr. Ganesh, Dr. Pe’er and colleagues also found that metastatic cancer cells demonstrated greater multilineage potential in response to microenvironment cues than their lineage-restricted primary tumor counterparts. Using patient-derived organoids, they observed the transcription factor PROX1 stabilized intestinal lineage in the fetal progenitor state.
Dr. Ganesh noted that non-canonical gene signatures could serve as biomarkers of future disease relapse and poor survival and be clinically useful for identifying patients most likely to benefit from aggressive neoadjuvant or adjuvant therapy targeting non-canonical states to prevent future metastasis.
Read AACR Abstract 367. The study was supported by grants from the National Institutes of Health, the Howard Hughes Medical Institute, an AACR NextGen Grant for Transformative Cancer Research, and the Gerry Metastasis and Tumor Ecosystems Center. It was also supported by the following awards: Damon Runyon Clinical Investigator Award, Stand Up to Cancer Convergence Award, Pershing Square Sohn Prize, Starr Cancer Consortium, and a Josie Robertson Investigator Award.
Access disclosures for Dr. Ganesh and Dr. Pe’er. Explore MSK clinical trials for colorectal cancer.
Evolutionary Dynamics of Whole-Genome Doubling in Ovarian Cancer
AACR 2024 NextGen Star Ignacio Vázquez-Gárcia, PhD, a postdoctoral fellow working in the Sohrab Shah Lab at MSK, was an invited speaker for the session entitled Mutational Processes in Cancer: From Replication Stress to Complex Genomic Rearrangements. He shared the latest findings from MSK SPECTRUM, a collaborative effort focused on high-grade serous ovarian cancer (HGSOC), the most common and lethal gynecologic malignancy. Comprising about 70% of epithelial ovarian carcinomas, HGSOC accounts for 90% of advanced-stage disease and mortality.
Dr. Vázquez-Gárcia and colleagues discovered whole-genome doubling is a pervasive and active evolutionary process in HGSOC. Specifically, they found that elevated rates of chromosomal missegregation, multipolar cell division, and micronucleus rupture drive tumor progression. Their work also revealed that whole-genome doubling enables both early and late clonal diversification, modulates cell cycle progression, and leads to the development of immune-suppressive phenotypes.
The current discoveries added to previous research published by first author Dr. Vázquez-Gárcia and colleagues in Nature in December 2022, which detailed their findings on how ovarian cancer mutational processes evade the immune system. For their multimodal analysis in these studies, they performed single-cell whole-genome sequencing, single-cell RNA sequencing, multiplexed immunofluorescence, and digital pathology on 160 primary and metastatic tumors from 42 patients diagnosed with HGSOC who underwent surgery at MSK.
Dr. Vázquez-Gárcia said the team hopes their findings could help identify therapeutic vulnerabilities to selectively target genomically unstable cancer cells and lead to the development of treatment strategies that improve survival outcomes for patients with HGSOC.
The MSK SPECTRUM team consists of experts from many disciplines across many MSK labs and departments, including the Sohrab Shah Lab (Epidemiology and Biostatistics); the Integrated Genomics Operation; the Marie-Josée and Henry R. Kravis Center for Molecular Oncology; ovarian medical oncology, surgery, radiology, and pathology; the Parker Institute for Cancer Immunotherapy; the Britta Weigelt Lab (Memorial Hospital Research Laboratories); and MSK MIND (Multi-Modal Integration of Data).
Read AACR 2024 Abstract 11771. Dr. Vázquez-Gárcia and colleagues’ research was funded by the Ovarian Cancer Research Alliance, Cycle for Survival (MSK and Equinox), the U.S. Department of Defense, the Center for Integrated Cellular Analysis, the Leslois Shaw Foundation, Break Through Cancer, and the Seidenberg Family Foundation.
Access disclosures for Dr. Shah and Dr. Bakhoum. Explore MSK clinical trials for ovarian cancer.
Other Notable MSK Research News from AACR 2024:
- Developing CAR T Cells for High-Grade Serous Ovarian Cancer. MSK physician-scientist Scott Lowe, PhD, Scott W. Lowe, PhD, Chair of the Cancer Biology and Genetics Program at the Sloan Kettering Institute, and members of the Scott Lowe Lab have developed CAR T cells targeting the urokinase plasminogen activator receptor (uPAR), which is overexpressed in a wide range of cancer types, including pancreatic, kidney, bladder, brain, and ovarian carcinomas. Dr. Lowe and members of his lab have found that human uPAR CAR T cells can eliminate primary and metastatic human high-grade serous ovarian cancer tumors in xenograft models. Read AACR Abstract 975, part of the Tumor-Induced Immune Suppression 1: Extrinsic Factors session, presented by lead author postdoctoral researcher Zeda Zhang, PhD. Access disclosures for Dr. Lowe.
- Minimal Residual Disease Assessment in Solid Tumors: The Path to High-Value Clinical Applications. Physician-scientist Luis Diaz, Jr., MD, head of the Division of Solid Tumor Oncology and Grayer Family Chair at MSK was an invited speaker for the AACR-ASCO Joint Session on Detecting Minimal Residual Disease (MRD) and How to Apply it in the Clinic. Dr. Diaz’s presentation covered progress to date. Read AACR Abstract 68. Access disclosures for Dr. Diaz. Explore MSK clinical trials for colorectal cancer, pancreatic cancer, and bile duct cancer.