Andrew Koff, PhD, Member and Professor, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
2014 Heidi Connery Memorial Research Grant: “Proteomic and genomic approaches to understanding intrinsic and acquired resistance to CDK4 inhibition therapy in well differentiated/dedifferentiated liposarcoma”
PLEASE DESCRIBE THE FOCUS OF THE RESEARCH PERFORMED IN YOUR LAB.
The laboratory of cell cycle regulation at Memorial Sloan Kettering Cancer Center is interested in identifying the genes and proteins that regulate the transition of cells from quiescence, a reversible type of proliferative exit, to senescence, a more stable irreversible type of proliferative exit. Proliferation associated with a deregulated cell cycle underlies the expansion and development of many cancers and thus understanding how cells exit the cell cycle and adopt these non-proliferative fates is a key area in which to attack the development of cancer.
WHAT HAS INSPIRED YOU TO RESEARCH SARCOMA?
The deregulation of cell cycle exit is a fundamental process that occurs in cancer, and as such the laboratory has studied this process in many different types of cancer, including oligodendroglioma, breast and prostate cancer, as well as in various developmental systems such as muscle, blood vessel, and ovary. We have employed biochemistry, cell biology, and mouse models to investigate this process.
In the last five years we have strived to understand what happens after cells exit the cell cycle and focused on the senescence after quiescence decision. As it became clear that understanding this pathway could have a significant impact on treatment outcomes we needed to find a community that was both engaged by the science and enthusiastic to translate findings into patients. You, in soft tissue sarcomas, are truly that community.
The investigative group at Memorial who treat patients (Mark Dickson, William Tap and in the past Gary Schwartz) had been developing cdk4 inhibitor based therapies in sarcoma (cdk4 is an enzyme that is very important for cells to commit to the cell cycle, and inhibition of it causes them to exit the cell cycle). Surgeons at Memorial (Sam Singer, Aimee Crago) were amenable to providing samples and cell lines, clinicians who were treating the patients were amenable to enrolling patients into clinical trials and discussing outcomes with us, pathologists (Cristina Antonescu) were excited to help us develop potential markers, and we at the Sloan Kettering Institute (myself, David Liu, Marta Kovatcheva and Mary Klein) were excited to tackle the question of how cells that exit the cell cycle make decisions regarding their proliferative fate. Thus our inspiration to research sarcoma stemmed from the willingness of your community and clinical collaborators at Memorial to get things done. Indeed, over the last ten years Memorial Sloan Kettering Cancer Center has solidified their commitment to supporting a collaborative environment between researchers and clinicians with the establishment of a new Graduate program for research oriented PhD students to inspire them to delve deeply into basic science and apply it to clinical problems (the Louis V. Gerstner Graduate School of Biomedical Sciences). Kovatcheva and Klein were students in this training program.
PLEASE SHARE A BIT ABOUT THE PROJECT THAT WAS FUNDED BY YOUR SFA RESEARCH GRANT AWARD.
This project followed on seminal studies by Kovatcheva, Liu and Klein who established that the efficacy of CDK4i to retard progression of well differentiated and dedifferentiated liposarcoma was associated with the down regulation of a gene product known as MDM2. MDM2 downregulation associated with CDK4 inhibition led to senescence. Thus, it was clear that CDK4i would induce cell cycle exit (quiescence) but there were later events that were required to promote the further transition to senescence (irreversible cell cycle exit). One such event requires ATRX, a chromatin remodeling protein that we discovered to be important for this transition. The work supported by the Heidi Connery Memorial Award was to understand how ATRX was working—what the mechanism of action was.
This resulted in our finding that as cells move into senescence, ATRX represses the expression of a gene called HRAS. HRAS has a long storied history in cancer biology (in fact it was one of the first oncogenes discovered) and over the last 25 years drugs targeting it have been developed, but have had little clinical impact as single agents. What this work does is place the role of HRAS, not at cell proliferation where people had been looking, but rather after cells exit the cell cycle. Thus, we hypothesize that combinations of cdk4 inhibitors with HRAS inhibitors in sequential application may become more useful for patients. Some of the current work in the laboratory is now focused on directly addressing this hypothesis with the hope that we can nominate new therapeutic combinations into clinical practice of well differentiated and dedifferentiated liposarcoma.
HOW HAS FUNDING FROM THE SARCOMA FOUNDATION OF AMERICA HELPED IN YOUR RESEARCH EFFORTS?
Without this award when we initially began, the work would not have been pushed towards this goal. Now that the first papers are out (2015 and 2017) and others are being written, other groups are learning how important such decisions in quiescent cells are, not only to cancer therapy but also in the process of tumor dormancy during metastatic seeding and perhaps normal aging. We are now busily writing additional grants to obtain federal funding for continuing such studies and are discussing new clinical trials with a number of pharmaceutical companies to leverage the understanding we have gained during the projects funded by this grant with the hope that we may be able to slow the development of soft tissue sarcoma and other diseases.