Mentor Areas
My laboratory has a long-standing interest in pathobiology of hematologic and some solid cancers, with strong emphasis on non-coding RNAs and aberrant gene regulation at the RNA level. Since 2008, my lab is located at the Children's Hospital of Philadelphia, where it is an integral part of the Center for Childhood Cancer Research. This integration allowed me to foster new collaborations with key physician-scientists and pursue several translational projects, including our discovery of the role of alternative splicing in resistance to immunotherapy. Our current work is supported by the National Cancer Institute Moonshot Initiative through the Pediatric Immunotherapy Discovery and Development Network (PI-DDN).
Description:
Successful immunotherapies for childhood cancers typically target lineage-, rather than cancer-specific markers, B-cell specific CD19 being the prime example. These successes culminated in the recent FDA approval of bi-specific T-cell engagers and chimeric antigen receptor (CAR)-armed T-cells for B-cell acute lymphoblastic leukemia (B-ALL). However, relapses frequently occur in patients treated with CD19-directed immunotherapies, often due to epitope loss. While strategies based on dual antigen targeting are beginning to emerge, they are still based on targeting canonical B-cell markers, with the unavoidable side effect of total ablation of normal B-cells. The apparent paucity of tumor-specific targets in pediatric cancers (including leukemias) is likely to limit future immunotherapies. We hypothesize that alternative splicing could be both a mechanism of epitope loss and a rich source of a neo-antigens in B-ALL. Indeed, using computational and biochemical approaches, we have identified hundreds of local splicing variations (LSVs), mapping to transmembrane proteins (e.g., CD19 and CD22) with prominent extracellular domains (ectodomains). In fact, in our prior work we described a mechanism of acquired resistance to CART-19 based on selective loss of the CD19 ectodomain, primarily through exon 2 skipping. Our current aims are as follows. Aim 1 is to identify programs and determinants of altered splicing of B-ALL cell surface antigens. Aim 2 is to investigate the effects of alternative splicing on B-ALL immunotherapy. Using CD22 as just one example, we will determine how truncated protein isoforms confer resistance to CD22-targeting immunotherapeutics. We will also raise antibodies against peptides spanning novel exon junctions, generate antibody-drug conjugates, and test their efficacy against B-ALL cell lines and patient-derived xenografts. In summary, this project will create new computational and conceptual frameworks, which would allow identification of antigenic epitopes that are uniquely expressed on childhood cancers and of cancer cell-intrinsic mechanisms of immune evasion.
Preferred Qualifications
Familiarity with basic cell and molecular biology techniques; intro level biology courses; interest in cancer research
Details:
Preferred Student Year
Second-Year, Junior, Senior
Academic Term
Fall, Spring, Summer
I prefer to have students start during the above term(s).Volunteer
Yes
Yes indicates that faculty are open to volunteers.Paid
No
Yes indicates that faculty are open to paying students they engage in their research, regardless of their work-study eligibility.Work Study
Yes
Yes indicates that faculty are open to hiring work-study-eligible students.