The Goel Lab studies the cell cycle machinery in cancer, focused on the ways cell cycle proteins drive cancer progression and how they can be targeted
At the Goel lab, we study the cell cycle machinery and how it influences cancer biology in both cancer cells and stromal cells. We leverage our discoveries to design new drug therapies for cancer, and play a leading role in trials aiming to bring these therapies to the clinic.
Many cancer therapies activate the RB and/or p53 tumour suppressors, and in doing so induce a cellular phenotype that resembles cellular senescence. These senescent cancer cells are resistant to nearly all existing cancer therapies and thus form a reservoir of cells that can fuel tumour progression and relapse. In non-cancerous cells, cellular senescence is associated with dramatic alterations in cancer cell metabolism, epigenetic profile, and kinase signalling. However, it is not clear whether these features of classical senescence are recapitulated in tumour cells that have entered. Using a variety of in vitro and in vivo approaches, we are exploring the nature of therapy-induced senescence, searching for changes in cancer cell biology that expose new therapeutic vulnerabilities.
One of the biggest challenges in cancer biology is to understand dormancy and late relapse. Why do some cancers lie dormant for many years, only to re-emerge and cause life-threatening illness? One of the reasons we don't understand dormancy is that it is very hard to study in the lab. We have developed new models of dormancy that allow us to see and study dormant cancer cells in unprecedented detail, and are using our insights to design new treatments to prevent cancer relapse.
The majority of patients with metastatic breast cancer will receive a CDK4/6 inhibitor as part of their treatment. Although these drugs are highly effective in most cases, tumours almost invariably acquire resistance to CDK4/6 inhibitors over time. DNA sequencing studies have failed to uncover mutational causes for this resistance in the majority of cases. Indeed, for most of our patients, we have no understanding of why their tumour has developed CDK4/6 inhibitor resistance and thus have no good strategies to overcome it. Using unique mouse and cell line models, we are exploring novel, non-mutational mechanisms of CDK4/6 inhibitor resistance. We also lead clinical trials exploring new therapies with the potential to overcome CDK4/6 inhibitor resistance.
Although several preclinical studies have now demonstrated that CDK4/6 inhibitors enhance anti-tumour immune responses, the precise mechanisms by which this occurs are still poorly understood. In collaboration with colleagues with expertise in immunology and bioinformatics, we are analyzing how CDK4/6 inhibitors alter intratumoural immune cell number and function in unprecedented depth. We believe this research will help determine the ideal immunotherapy partners for CDK4/6 inhibitors. We are also leading clinical trials that seek to exploit this mechanism of CDK4/6 inhibitor activity.