Blake R. Wilde, PhD

Decades of research on cancer metabolism has addressed how metabolism supports growth of established tumors; however, little is known about the role of metabolites in regulating oncogenic initiation and the evolutionary trajectories of tumors. Our overarching goal is to conduct research that elucidates the mechanisms by which metabolites regulate oncogenic initiation, all while innovating strategies to target metabolism for therapeutic gain.

1. Oncometabolite-driven tumor initiation

The central role of metabolism in tumor initiation is highlighted by the discovery of oncometabolites, which are metabolites that can drive tumorigenesis when aberrantly accumulated. Our prior work on fumarate-driven kidney cancers provided mechanistic insight into how fumarate drives tumor growth and serves as a platform for investigating the role of fumarate and other oncometabolites in oncogenic initiation. As a proof of concept, we investigate fumarate- and succinate-driven tumors, which accumulate the oncometabolites fumarate and succinate, respectively. Long-term, we envision exploring the more nuanced role of metabolites in regulating the initiation of many tumor types.

2. Fixed metabolic requirements of tumor initiation

Cancers rewire metabolism to meet increased bioenergetic and biosynthetic demands, often developing dependencies on specific metabolic pathways. Exploiting these fixed metabolic requirements provides a promising avenue for cancer therapy. The success of antimetabolite chemotherapies highlights the clinical potential of targeting metabolism. By identifying key metabolic liabilities in tumor initiation and progression, we seek to inform new therapeutic strategies aimed at preventing cancer development.

3. Hereditary cancer syndromes and metabolic interventions

Patients with hereditary cancer syndromes, who carry an elevated lifelong risk of developing cancer, have an urgent need for effective strategies to prevent cancer. Current options, such as enhanced surveillance and prophylactic surgeries, are invasive and often come with significant physical and emotional burdens. A deeper understanding of how metabolic alterations contribute to early tumor development could reveal new opportunities for intervention. By targeting these vulnerabilities before malignancy arises, we aim to develop metabolically driven strategies to prevent cancer at its earliest stages.