Grantees
2023 Lion Heart Grant recipients addressing the Lion Hearts during the team dinner: Rachel Perry, Stacy Malaker, Arnaud Augert, Ngozi Akingbesote.
2023 Lion Heart Grant recipients
For the 12th consecutive year, the Lion Heart Grant Committee met on December 19 at Smilow Cancer Hospital’s Breast Center to review and choose our 2024 research grants. For 2024 we awarded three $ 50,000 grants:
Grantees for 2024
Developing CAR-mast cell therapy for breast cancers
Principal Investigator: Xiaolei Su, PhD. Assistant Professor of Cell Biology, Yale School of Medicine
Co-Investigators: Sidi Chen, PhD, Associate Professor of Genetics and Neurosurgery, Yale School of Medicine Christopher Kepley, Associate Professor of Nanoscience, University North Carolina Greensboro
New high-impact cancer therapies harness the patient’s immune system to attack their cancers. Combination therapies including immune checkpoint inhibitors that release restraints on anti-tumor responses of T cells have moderate efficacy in breast cancer and have been approved by the FDA. Another new approach is Chimeric antigen receptor-T (CAR-T) therapy, in which a patient’s T cells are engineered to recognize and attack specific molecules expressed by cancers. While CAR-T therapies have been extraordinarily successful for controlling some blood cancers, they have not shown much utility on solid tumors including breast cancer. Reasons include challenges in maintaining stable T cell localization at tumors, the generally immune suppressive neighborhood of tumors, and exhaustion of activated T cells. T cells are only one cellular component of effective immune responses, and recent findings indicate that another type of immune cells, mast cells, can inhibit tumor growth as well. Hence Dr. Su plans to open a new area of research by engineering mast cells to recognize tumor cells and alert other immune cells including the patient’s T and Natural Killer cells so that a coordinated anti-tumor response will be mounted. Use of CAR-mast cells should circumvent some of the practical problems leading to failure of CAR-T therapies, especially as mast cells reside in sites for long periods of time, and can be expected to continue to produce factors for prolonged recruitment of T cells and other immune cells to the tumors and maintenance of a more immune-active microenvironment local to the tumor cells. Moreover, it is expected that the CAR-mast cells engineered to recognize will collaborate with the patient’s T cells and natural killer cells to provide a powerful and coordinated anti-tumor immune response. The technical approach uses the same general strategy as used for CAR-T production, but include an innovative screen for optimal signaling domains to be fused with the tumor targeting domains that bind HER2 or GD2 proteins upregulated in breast cancers. Dr. Su anticipates that working with mast cells will circumvent known issues limiting success of CAR-T in breast cancer.
This exciting proposal builds on Dr. Su’s leadership investigation of immune cell signaling. Drs. Chen and Kepley add expertise in genome editing and mast cell biology, respectively. Success will introduce a new mode of therapy (CAR-mast) into the immune modulation armamentarium that will advance efficacy of adoptive cell therapies in breast cancer and are expected to have major impact in combination with immune checkpoint therapies.
Development of chimeric antigen receptor (CAR) T cells targeting MET in metastatic triple negative breast cancer
Principal Investigator: Po-Han Chen, MD, PhD Instructor in Hematopathology, Dept. of Pathology, Yale School of Medicine
Co-Investigator: Samuel Katz, MD, PhD Associate Professor of Pathology, Yale School of Medicine Collaborator: Qin Yan, PhD Professor of Pathology, Yale School of Medicine
Chimeric antigen receptor (CAR)- T cell therapies, in which a patient’s T cells are engineered to recognize cancer cells, have been successful for controlling of some blood cancers, but are ineffectual against solid tumors such as breast cancers. The reasons include limited choice of targeting molecules in breast cancer and early exhaustion of T cell populations that do find their tumor target. Dr. Chen will engineer T cells to express an antibody targeting them to MET, a protein that is overexpressed in triple negative breast cancers using state-of-the-art CAR-T production methods and is also a therapeutic target for drug resistance. The fact that
MET has been targeted in other contexts for cancer therapy means that there is some information on expected toxicity profiles that will accelerate translation to the clinic if the method is effective in model systems. T cells targeted to MET-expressing breast cancers are expected to kill tumor cells through the “extrinsic” cell death pathway. Dr. Chen will further test the hypothesis that the lethality of these engineered T cells will synergize in combination with cell death agonists that sensitize tumor cells to killing through this mechanism and have some efficacy as TNBC monotherapies.
This funding will not only support an innovative new CAR-T targeting approach but will further help launch Dr. Chen as an independent junior scientist who has specialized training in immuno-oncology. Dr. Katz provides expertise through his own experience in mechanisms of cell death and design and production of CAR-T cells, and Dr. Yan contributes experience in cell culture and animal modeling to understand and treat breast cancer.
Investigating a novel epigenetic mechanism in breast cancer
Principal Investigator: Andrew Xiao, Ph.D. Associate Professor of Genetics, Yale School of Medicine
Epigenetic regulators trigger cancer development and resistance to therapies through two general mechanisms. First, they can operate much like DNA mutations in imposing stable changes that activate or suppress expression of individual genes. For example, extinguishing expression of a tumor suppressor gene will have the same impact as mutating that gene, since both mechanisms prevent the gene product from doing its job. Secondly, epigenetic regulators jointly regulate many genes, and can even switch cells across to different general states or identities. This can promote or interfere with the ability of tumor cells to evolve and eventually escape the effects of cancer therapies. Histones are proteins that package the entire genome and are important mediators of epigenetic regulation. There are several forms of histones, each of which has specialized functions. One of the poorly characterized histone variant is highly expressed in subsets of breast cancers. Dr. Xiao’s laboratory has shown that this histone variant forms a complex with a major breast cancer tumor suppressor, where it presumably alters the ability of the tumor suppressor to modulate expression of target genes and processes including cell division and stem-like cell properties. The plan is to investigate the involvement of this histone variant in recruitment of the tumor suppressor to its DNA target sites, and the impact on regulation of its well-characterized targets. Since this tumor suppressor gene is only one of many genes that may be affected by this histone variant. Aim2 will evaluate differences in DNA bound sites of this histone variant across breast cancer subtypes and determine the impact of this histone variant on breast cancer phenotypes including progression, stemness, and invasiveness. This work will be done using patient-derived xenograft models that retain high fidelity to the tumor of origin.
Dr. Xiao is a leader in developmental epigenetics with an established cancer research program, but new to breast cancer research. Success of this pioneering research on this histone variant will advance understanding of a poorly understood category of epigenetic regulators that has been linked to breast cancer, and may deepen understanding of a significant breast cancer tumor suppressor. This work may in the long run lead to new therapeutic approaches to control breast cancer.