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Researchers at the National Cancer Institute (NCI) have identified two novel molecular targets, annexin 1 (Anx A1) and its receptor formyl peptide receptor 1 (FPR1), for new anti-glioblastoma therapies. Anx A1 and FPR1 mediate growth, invasion, production of angiogenic factors, tumor formation, and are abnormally expressed by more highly malignant glioblastomas. Depletion of Anx A1 in glioblastoma cells resulted in their reduced capacity to form tumors; additional depletion of FPR1 further reduced this capacity. Further, the NCI researchers have found a correlation between Anx A1 expression and the degree of malignancy of human gliomas.
Novel anti-glioblastoma therapies encompassed by this invention include neutralizing antibodies against Anx A1 and FPR1, small compound agonists of Anx A1 and FPR1, small interference RNAs (siRNAs) that deplete Anx A1 and FPR1 from glioblastoma cells, as well as delivery methods to effectively administer the Anx A1 and FPR1 targeting drugs into brain tissues.
* Treatment of glioblastoma multiforme and other brain tumors.
* Treatments for inhibiting neoplastic cell growth.
* Treatments for inhibiting tumor progression and metastasis.
* Treatments for inhibiting angiogenesis in a tumor.
* High specificity.
* Does not require radiation.
* A correlation between expression of the molecular target and the degree of tumor malignancy is known.
* Wide-range/flexibility of potential therapies and approaches.
T cell receptors (TCRs) are proteins that recognize antigens in the context of infected or transformed cells and activate T cells to mediate an immune response and destroy abnormal cells. TCRs consist of two domains, one variable domain that recognizes the antigen and one constant region that helps the TCR anchor to the membrane and transmit recognition signals by interacting with other proteins. When a TCR is stimulated by an antigen, such as a tumor antigen, some signaling pathways activated in the cell lead to the production of cytokines, which mediate the immune response.
Scientists at the National Institutes of Health (NIH) have developed T cells genetically engineered to recognize synovial sarcoma X breakpoint-2 (SSX-2) peptide antigens. SSX proteins, including SSX-2, are expressed primarily by tumor cells from a variety of cancers, including pancreatic cancer where very few treatment options exist. Other than germ cells of the testis, normal cells do not express SSX proteins and, thus, should not be targeted by therapies directed against these proteins. Therefore, SSX proteins represent a promising target for cancer immunotherapy. There are ten (10) known members of the SSX protein family designated SSX-1 through SSX-10. The T cell receptors (TCRs) developed by these NIH scientists have specificity for SSX-2 and deliver a robust immune response when they encounter SSX-2 expressing cells. However, these TCRs also recognize five (5) other SSX family members, including SSX-3, SSX-4, SSX-5, SSX-9, and/or SSX-10, and deliver a productive, intermediate immune response in the context of target cells expressing these antigens. This versatile antigen coverage could allow these SSX-specific TCRs to be utilized in the treatment of multiple types of cancer in a wide array of cancer patients. Infusing cancer patients with SSX-2 specific T cells via adoptive immunotherapy could prove to be a powerful approach for selectively attacking tumors without generating toxicity against noncancerous cells.
* Immunotherapeutics to treat and/or prevent the recurrence of a variety of human cancers, including pancreatic cancer and melanoma, by adoptively transferring the gene-modified T cells into patients whose tumors express a SSX family member protein recognized by this TCR.
* A drug component of a combination immunotherapy regimen aimed at targeting specific tumor-associated antigens, including SSX-2, SSX-3, SSX-4, SSX-5, SSX-9, and/or SSX-10 expressed by cancer cells within individual patients.
* A research tool to investigate signaling pathways in SSX-2 expressing cancer cells.
1. N Chinnasamy,
2. D Valmori,
3. G Bricard,