The focus of our lab is to develop a novel type of anti-cancer immunotherapy which is based on a novel type of immunotherapeutic targets. Our approach is based on the following fundamental principles: 1) cells experiencing DNA damage repress transcription of many cell cycle-related genes; 2) cells with a mutated p53 gene are unable to mediate this transcriptional repression, creating a clear transcriptional difference between normal and cancer cells within a host; 3) certain chemotherapies (e.g., topotecan, 5-Fluorouracil, etc.), in addition to causing DNA damage, cause abnormal splicing leading to generation of abnormal transcripts that are recurrent and reproducible in cells treated with such chemotherapy; 4) the abnormal splicing products undergo Nonsense Mediated mRNA Decay, but not before a Pioneer Round of translation, which is known to create antigenic epitopes. Based on this principles we found that 1) selected chemotherapies lead to generation of products of abnormal splicing (Products of Abnormal Splicing Induced by Chemotherapy or PASIC) that are not expressed in untreated cells or in treated cells with a functional p53, and 2) PASIC create new and predictable neo-epitopes or chemo-neo-epitopes, immunization with which, before chemotherapy will lead to immunity against the tumor subjected to chemotherapy thus contributing to tumor eradication. PASIC neo-epitopes have the following advantages over all other tumor antigens: 1) chemo-neo-epitopes are shared between cancers treated with the same chemotherapy, thus eliminating enormous logistical hurdles. 2) The chemo-neo-epitope vaccine addresses the issue of heterogeneity by not requiring tumor tissue. The chemo-neo-epitopes are created uniformly in all cancer cells exposed to chemotherapy. 3) Chemo-neo-epitopes are not expressed physiologically in the adult or embryonic tissues, in normal cells or cancer cells. They are expressed solely upon exposure of the host to selected chemotherapies. They are not therefore subject to central deletion or peripheral tolerance, and consequently can generate very strong immune response.
The other targets for the anti-cancer immunotherapy are abnormal splicing-generated neo-epitopes that correspond to distinct oncogenic pathways. A particular example is the breast cancer with PIK3CA pathway activation. The mutations in the PIK3CA gene, the most commonly mutated gene in breast cancer, can cause recurrent abnormal splicing. The specificity to cancer of products of the abnormal splicing events mediated by mutations in PIK3CA gene is based on the PIK3CA kinase capability to upregulate ATP-dependent RNA helicase DDX5, which is involved in spliceosome assembly and in the alternative regulation of pre-mRNA splicing. Also, Gene Set Enrichment Analysis (GSEA) of genes dysregulated by mutational activation of PIK3CA revealed the enrichment for gene sets associated with the spliceosome, suggesting that the pattern of splicing will be different between PIK3CA mutant and PIK3CA wild type cells thus creating cancer specific-neo-epitopes.
We work on providing the evidences that the strong immune response induced by prior vaccination of cancer patients with peptides corresponding to chemo-neo-epitopes generated during chemotherapy by aberrant splicing will result in the efficient elimination of cancer cells. The effect of simultaneous action of both immuno- and chemotherapy can be much stronger than the effect from each treatment alone. We use a mouse model of breast cancer to demonstrate the efficiency of this novel type of combining of chemo- and immunotherapy to treat metastatic breast cancer.
Development of novel cancer immunotherapy approach based on shared chemotherapy-induced neoepitopes.
Identifying chemotherapy-induced neoepitopes generated by abnormal splicing events specific for distinct oncogenic pathways.