AbstractUnderstanding the comprehensive interactions between genetic changes, epigenetic dysregulation, aberrant metabolism and immune evasion in cancer provides a deeper insight into its pathogenesis and progression, and helps identify vulnerabilities for therapeutic exploration. This Commentary highlights a series of published studies uncovering the following: molecular mechanisms and prognostic impact of aberrant DNA methylation/hydroxymethylation in clear cell renal cell carcinoma (ccRCC) which accounts for 80% of all kidney cancers; the potential of ascorbic acid (AA) in reversing aberrant methylation in cancers (ccRCC and lymphoma) via activation of the Ten-Eleven Translocation (TET) enzymes in vitro and in vivo; AA-induced demethylation and re-expression of tumor-suppressors and endogenous retroviral transcripts in lymphoma cells; mechanistic and anti-tumor synergy between high-dose AA and anti-PD1 immunotherapy in a lymphoma mouse model; and important considerations while exploring the potential of AA as an anti-cancer agent in vitro and in vivo to enhance translation of pre-clinical findings.
These findings have led to two actively accruing multi-center phase 2 randomized trials combining IV ascorbic acid with standard of care treatment in ccRCC and diffuse large B cell lymphoma (DLBCL). They also provide a compelling rationale for testing combinations of high-dose AA and anti-PD1 agents in patients with aggressive B cell lymphoma and in preclinical models of other malignancies.
|Date of Award
|Sassan Hafizi (Supervisor)