AACR-MPM Oncology Charitable Foundation Transformative Cancer Research Grants Fund Innovative and Unconventional Projects

“Risky and rather unorthodox,” Sahand Hormoz, PhD offers when asked to describe the project funded by his 2019 AACR-MPM Oncology Charitable Foundation Transformative Cancer Research Grant.

Why risky and unorthodox? Hormoz, an assistant professor with the Department of Systems Biology at Harvard Medical School and the Department of Data Science at Dana-Farber Cancer Institute, had proposed to reconstruct the evolutionary history of individual cancer cells in order to determine how myeloproliferative neoplasms (MPNs), a group of rare blood cancers in which the bone marrow produces too many red blood cells, white blood cells, or platelets, originate and progress in individual patients. “We basically borrowed ideas from the field of phylogenetics that have been applied to species and evolutionary time scales to understand the evolution of cancer in each patient,” Hormoz explains. Instead of looking for the common ancestor of, for instance, humans and chimpanzees, he would seek the common ancestor of all a patient’s cancer cells.

In order to do so, Hormoz and his lab have developed an innovative single-cell profiling technology platform that allows for whole-genome sequencing of individual cells simultaneously with their transcriptional profiles and somatic mutations. This platform can further distinguish cancer cells from healthy cells. By using the pattern of somatic mutations accrued by the cells in MPN patient bone marrow biopsies, Hormoz can reconstruct the evolutionary history of individual cancer cells. Then with the aid of mathematical models he infers the history of disease progression in individual patients, including approximating when the first cancer-causing mutation occurred.

Initial findings from Hormoz’s unconventional project have already resulted in a publication in Cell Stem Cell. “To our surprise,” he says, “we found that in two individuals the cancer-causing mutation had occurred decades before diagnosis: at nine in the 34-year-old patient and at 19 in the 63-year-old patient.”

These findings have significant implications for the treatment of MPNs, which are currently incurable and can moreover evolve into a more aggressively lethal acute leukemia. “If the disease-causing mutation occurs decades before diagnosis, we should be able to detect the mutated cells and eradicate them before cancer emerges,” Hormoz surmises. “This would involve developing new tools for detection and screening,” he continues, “but with the right therapeutic interventions, we might be able to prevent the cancer from ever occurring in our patients.”

Hormoz’s research points to the potential of cancer intervention and epitomizes the key aims of the AACR-MPM Oncology Charitable Foundation Transformative Cancer Research Grant program: to fund projects that approach major problems and challenges in cancer research in innovative ways and that will likely have a transformative impact on future clinical practice.

Robert Eil, MD continues to realize the objectives of this grant program with his 2020 AACR-MPM Oncology Charitable Foundation Transformative Cancer Research Grant project. Eil, an assistant professor in the Departments of Surgery and Cellular, Developmental and Cancer Biology at Oregon Health & Science University, is tackling tumor immune evasion, a critical issue in cancer immunotherapy, from a unique angle.

“Many cancer researchers previously thought that cancer cell death acted to only stimulate the local immune response,” Eil explains, “but I’ve found that cancer cell death also results in the release and accumulation of potassium within tumor tissue, which results in profound suppression of the neighboring immune cells, preventing them from attacking the cancer cells.”

Using human intrahepatic cholangiocarcinoma (ICC) samples as a case study, Eil and his lab group are further investigating the functional significance and precise mechanisms of this newly discovered means of tumor immune evasion in order to figure out how to counter it with novel therapeutic strategies. Specifically, Eil hopes to use drugs and genetic engineering to augment the capacity of immune cells to resist the suppressive effects of high potassium levels, thereby reinvigorating their function within the tumor.

If successful, Eil’s project has the potential to provide oncologists with a new tool to target cancers resistant to currently available immunotherapies. And the AACR-MPM Oncology Charitable Foundation Transformative Cancer Research Grant program has provided the foundation for this exciting research.

“As a junior investigator starting out independently there is a lot of uncertainty,” Eil notes. “This award provides me with the stability to expand my research vision and the freedom to not have to limit myself to the safe, incremental advance of knowledge.” Just as intended.

Letters of Intents are currently being accepted from early- and mid-career investigators for the 2021 AACR-MPM Oncology Charitable Foundation Transformative Cancer Research Grants. The deadline for submission is June 29. Please visit the AACR’s funding page for more information.