Targeting the WNT Pathway to Reprogram the Tumor Microenvironment and Improve Immunotherapy of GBM
Abstract
Career Goals: My short term career goals are: (i) to develop an in-depth understanding of the glioblastoma (GBM) microenvironment and successfully exploit it for therapy, (ii) to complete the proposed project on targeting the WNT pathway to reprogram the tumor microenvironment and improve immunotherapy of GBM in a timely and successful manner, (iii) publish my results in high-impact journals, and (iv) network and collaborate with experts in the field. My long term goals are to become an independent investigator in GBM research and improve the survival of GBM patients. I intend to achieve these goals through the guidance of my mentor Dr. Rakesh Jain, who is a pioneer in the field of tumor microenvironment, bimonthly meetings with my advisory committee that includes neuro-oncologists, pathologists, and immunologists at Harvard, and quarterly meetings with patient advocates at the Dana Farber Cancer Institute. The expertise that I have gained in my mentors lab and training required in cutting edge techniques, attending seminars, courses, and workshops and presenting my work at important conferences are outlined in my individualized Researcher Developmental Plan. The proposed work will leverage my knowledge in GBM and my mentors expertise and resources (e.g., state-of-the-art animal facility with advanced GBM models) and extensive collaborations. Our lab is uniquely positioned to create effective treatment strategies that will be translatable to improve outcomes in GBM patients. The Horizon Award will be crucial and timely for achieving my career goals and helping patients. Scientific Objective and Rationale: GBMs are the most aggressive central nervous system tumors. GBM patients survive only for approximately 15 months, despite intensive treatments. Immunotherapy triggers the patients own T cells with a killing potential to attack the tumor. Tumors express certain proteins called checkpoints which weaken the killing potential of the T cells. Recently, a type of immunotherapy called immune checkpoint blockade (ICB) has revolutionized cancer therapy, but it has not benefited GBM patients to date. ICBs block the checkpoints on tumor cells and prevent the killing T cells from becoming weak, so that the T cells can attack and eliminate the tumor. However, ICBs also induce fluid accumulation and immune-related side effects such as problems with the skin, gut, liver, lung, and endocrine system. I therefore propose to identify potential barriers in GBM that prevent ICB therapy to work effectively and develop new strategies to overcome them. My strategy is to improve the efficacy of ICBs in GBMs by reprogramming the TME. Project Description: Both preclinical and clinical data indicate that components such as blood vessels, immune cells, and lack of oxygen can create an immunosuppressive TME and compromise the efficacy of ICBs. In this project, I will target two critical pathways in GBM in combination with ICB therapy, to reduce its toxicities and improve survival of preclinical models with the ultimate goal of inducing cures in patients: First, in my preliminary studies, I found that a signaling pathway, known as WNT, is elevated in GBM compared to normal brain in mice and patients. I also found that WNT is involved in invasion of GBMs and promotes immunosuppression by activating immune suppressor cells. LGK974 is an agent that can block WNT and hence stop invasion of GBMs. Second, my mentor Dr. Jain is widely known for the concept that tumor vessels are abnormal in their function, and this abnormality causes lack of oxygen and immunosuppression. Blocking certain proteins, known as VEGF and Ang2, using an antibody repairs tumor vessels and reduces immune suppression. In my proposed project, I will combine these two agents – LGK974 and A2V – to dramatically improve the efficacy of ICBs against GBM tumors grown in mice, with the ultimate goal of helping GBM patients. Military Benefits: Despite concerted effort over decades to
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910723
Entities
People
- Shanmugarajan Krishnan
Organizations
- Massachusetts General Hospital
- United States Army