Targeting the stress response machinery in pediatric T cell acute lymphoblastic leukemia (T-ALL)
Iannis Aifantis
PhDNew York University School of Medicine
Project Term: July 1, 2019 - June 30, 2022
Current intensive chemotherapy regimens to T cell acute lymphoblastic leukemia (T-ALL) patients come at the cost of serious side effects while a significant percentage of patients experience relapse. We have recently demonstrated that T-ALL is addicted to the function of a stress response pathway activated in the presence of proteotoxic stress. Here, we present a novel approach to exploit the altered dependency of T-ALL on stress responses and target leukemia-specific vulnerabilities.
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that results from the accumulation of genetic alterations (such as mutations) during the development of precursors of T cells, a type of white blood cells with critical role in the human immune system. Despite the improvements in patient outcomes after introduction of intensified chemotherapy, a significant percentage of patients do not respond to therapy or experience disease relapse after a transient initial response. Moreover, serious side effects, such as secondary tumors, severely compromise our therapeutic efforts especially in children. Therefore, there is an urgent need to identify more specific therapeutic targets and drug combinations.
In order to avoid therapy-induced side effects we need to identify strategies that target specifically cancer cells while sparing healthy cells. In addition, there is an urgent need to elucidate the mechanisms that result in resistance to therapy upon relapse. During carcinogenesis, cancer cells undergo various alterations in many cellular processes. This results in increased levels of biological stress. To cope with stress, cancer cells depend on pathways that relieve stress, known as stress response pathways. Importantly, healthy cells are not dependent on stress response pathways under baseline conditions, making drug targeting of this pathway a promising therapeutic approach. Understanding the biology of stress responses and its crosstalk with the cancer machinery is a major focus of our laboratory. Using novel animals models and pediatric patient samples, this proposal will focus on identifying the group of patients who will benefit from a promising drug that is currently in clinical trials for solid tumors. In addition, we will investigate whether targeting a potential Achilles’ heel for resistant T-ALL, in combination with current therapy may prevent or combat recurrent disease. In conclusion, with our proposed research we hope to therapeutically exploit a tumor supportive pathway on which both newly diagnosed and relapsed leukemia are dependent.