2020 & 2022 Grantee: Kenneth Olive, PhD
Research Project: Therapeutic Induction of Tumor Selective Ferroptosis in Pancreatic Cancer
Award: 2020 Pancreatic Cancer Action Network Translational Research Grant
Award Period: July 1, 2020 – June 30, 2022
Award Extension: 2022 Pancreatic Cancer Action Network Translational Research Grant Extension funded by Kenneth D. Custance and Gladys C. Custance, honoring the memory of Martha ‘Molly’ Reed Woodroofe
Award Period: July 1, 2022 – June 30, 2023
Dr. Kenneth Olive graduated from Bucknell University in 1998 and received a PhD in cancer biology from MIT in 2005. Working in the laboratory of Dr. Tyler Jacks, Dr. Olive studied tumor-associated mutations in p53 and also helped develop the widely utilized “KP” genetically engineered mouse model of advanced lung adenocarcinoma. During his postdoctoral fellowship in the laboratory of Dr. David Tuveson at the University of Pennsylvania and University of Cambridge, Dr. Olive established a translational infrastructure for evaluating new therapies in genetically engineered mice with pancreatic cancer.
Through this approach, Dr. Olive demonstrated that the desmoplastic stroma (dense tissue that surrounds and supports pancreatic cancer cells) of pancreatic tumors limits drug delivery, providing an explanation for why pancreatic tumors are difficult to treat. This has led to multiple investigational strategies to target pancreatic tumor stroma to improve chemotherapeutic efficacy.
Since joining the faculty of Columbia University Irving Medical Center in 2010, Dr. Olive focused on translational medicine for pancreatic cancer, with efforts in systems biology, cancer metabolism, tumor microenvironment, and precision medicine. He also built and directs the Oncology Precision Therapeutics and Imaging core within Herbert Irving Comprehensive Cancer Center (HICCC), serves as Co-Leader of the HICCC Translational Systems Oncology program and is Director of GI Translational Research within the Department of Medicine. Dr. Olive previously received a PanCAN Career Development Award in 2011, funded by Tempur-Pedic Retailers.
The ideal cancer therapy is a treatment that kills tumor cells without harming normal cells. Cells can be killed in a variety of ways, including through a recently discovered process called “ferroptosis.” This type of death occurs when a cell’s outer membrane is damaged by oxidation – a reaction with oxygen.
Cells normally use a natural amino acid – a building block of proteins – called cysteine to prevent membrane oxidation. Dr. Olive and his research team have found that pancreatic tumor cells in particular have very high levels of oxidation, but they also use a lot of cysteine to counteract the oxidation. This means the cancer cells are particularly dependent on cysteine to protect themselves from ferroptosis.
The investigators have shown in extensive preliminary data that depleting pancreatic tumors of cysteine can cause them to undergo ferroptosis, whereas normal cells are unaffected since they have lower levels of oxidation. In particular, Dr. Olive and colleagues evaluated a novel enzyme called cyst(e)inase, which breaks down cysteine in the blood, for its effects on pancreatic tumors using a genetically engineered mouse model of pancreatic cancer.
Strikingly, cyst(e)inase induced ferroptosis specifically in pancreatic tumors and not in the normal tissues of the mouse, resulting in elevated levels of cell death in the tumors.
By itself, cyst(e)inase did not completely cure the mice of their pancreatic tumors. Dr. Olive therefore proposes to combine cyst(e)inase with other agents that could sensitize the tumors to ferroptosis. Based on promising preliminary data, the team will test cyst(e)inase in combination with an immunotherapy drug and a targeted drug that blocks the activity of a protein called MEK. These studies will be carried out in a gold-standard genetically engineered preclinical model as well as in a novel model system developed by their team that utilizes thin living sections of human pancreatic tumors.
Project Overview: 2022 Extension
Dr. Olive was the recipient of a 2020 PanCAN Translational Research Grant for a project focused on a newly discovered way that cells can die, called ferroptosis. This type of death occurs when a cell’s outer membrane is damaged by oxidation – a reaction with oxygen. Cells normally use a natural amino acid – a building block of proteins – called cysteine to prevent membrane oxidation. Dr. Olive and his research team have found that pancreatic tumor cells have especially high levels of oxidation, which they counteract by using a lot of cysteine. This means that cancer cells are particularly dependent on cysteine to protect themselves from ferroptosis.
The Olive lab’s research has shown that depleting pancreatic tumors of cysteine can cause them to undergo ferroptosis while leaving normal cells unaffected, as the latter possess lower levels of oxidation. In particular, the team has evaluated a novel enzyme called cyst(e)inase – which breaks down cysteine in the blood – for its effects on pancreatic tumors using a genetically engineered mouse model of pancreatic cancer.
Strikingly, cyst(e)inase induced ferroptosis specifically in pancreatic tumors and not in the normal tissues of the mice, resulting in elevated levels of cell death in the tumors. By itself, cyst(e)inase did not completely cure the mice of their pancreatic tumors. Dr. Olive’s original project therefore proposed to combine cyst(e)inase with an immunotherapy approach and a drug that targets a protein called MEK.
Through his one-year Translational Research Grant Extension funding, Dr. Olive and his team will further evaluate the combination treatment approaches using a leading-edge technique that allows the investigators to study individual cells and understand how genetic material (DNA) gets transcribed to RNA, which is a critical step toward creating proteins that impact cellular behaviors.
There can be vast differences between cancer cells within a single tumor. Even malignant cells with identical DNA mutations can assume different states that vary in their biology, their genetic dependencies and their therapeutic vulnerabilities. Dr. Olive believes that the presence of cancer cells in different states within most pancreatic tumors underlies the ability of these tumors to resist treatment. By studying their different therapeutic sensitivities, the Olive lab is hoping to build combinatorial drug regimens that target the full range of variation within a patient’s tumor.
Dr. Olive and his colleagues have found that the impacts of MEK inhibition and cyst(e)inase treatment propagate through the tumor stroma, modulating the immunosuppressive tumor microenvironment. By studying how the cellular states of each distinct cell type within a tumor are impacted by treatment, they hope to develop a truly holistic understanding of therapeutic response and resistance, paving the way for refined regiments and future clinical testing in patients with pancreatic cancer.