Medicine and Health Sciences Commons^™

Relieving Immune Suppression In The Melanoma Tumor Microenvironment, Gretel Torres Santiesteban

Dartmouth College Ph.D Dissertations

The high immunogenicity of melanoma tumors makes these malignancies an attractive target for immunotherapeutic treatment, as evidenced by the success of ipilimumab and nivolumab. However, most immunotherapeutic approaches have had limited success, partly due to the suppression of innate and adaptive immune responses by tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). TAM redirection may relieve immunosuppression in the TME, directly inhibiting melanoma growth and potentially enhancing the efficacy of additional targeted and immuno-therapies.

We have shown that synthetic oleanane triterpenoid CDDO-Me (or C-Me) enhances immune activation in the melanoma TME by reprogramming TAMs from immunosuppressive to immunostimulatory. CDDO-Me is …

A Novel Caspase 8 Selective Small Molecule Potentiates Trail-Induced Cell Death, Octavian Bucur, Gabriel Gaidos, Achani Yatawara, Bodvael Pennarun, Chamila Rupasinghe, Jérémie Roux, Stefan Andrei, Bingqian Guo, Alexandra Panaitiu, Maria Pellegrini, Dale Mierke, Roya Khosravi-Far

Dartmouth Scholarship

Recombinant soluble TRAIL and agonistic antibodies against TRAIL receptors (DR4 and DR5) are currently being created for clinical cancer therapy, due to their selective killing of cancer cells and high safety characteristics. However, resistance to TRAIL and other targeted therapies is an important issue facing current cancer research field. An attractive strategy to sensitize resistant malignancies to TRAIL-induced cell death is the design of small molecules that target and promote caspase 8 activation. For the first time, we describe the discovery and characterization of a small molecule that directly binds caspase 8 and enhances its activation when combined with TRAIL, …