The lack of specific targets for triple negative breast cancer (TNBC) patients remains a major challenge as many are likely to fail standard therapy and develop recurrence within the first five years of follow-up. We have identified that an important regulator of the cell cycle, cyclin E, is over expressed in TNBC. This over expression is seen in the form of low molecular weight cleavage products of cyclin E, termed LMW-E, and is present in 70% of all TNBC compared with only 20% of non-triple negative tumors. The LMW-E have increased kinase activity over full-length cyclin E, are oncogenic in a transgenic mouse model and are a novel target for therapy. It is our goal to use LMW-E to identify TNBC patients, which can be targeted for therapy using Roscovitine (seliciclib), a clinically available inhibitor of LMW-E kinase activity. This therapy is most effective when delivered in combination with chemotherapy. TNBC cell lines are more susceptible to synergistic cytotoxicity with Roscovitine and chemotherapy as compared to normal and non-TNBC. Lastly, we show that induction of LMW-E results in genomic instability. As such, a combinatorial approach of Roscovitine with chemotherapy to exploit the genomic instability and impact on DNA damage pathways is warranted in TNBC patients. We hypothesize that LMW-E expression leads to generation of TN breast cancer and that targeting the LMW-E will provide novel targeted and effective therapeutic strategies for TN breast cancer. The following four Specific Aims will test this hypothesis: (1) Apply an integrated genomic-proteomic approach to identify key genes and proteins that drive the aggressive phenotype of LMW-E positive breast cancer as a function of molecular subtypes. (2) Use of in vitro and in vivo xenograft and transgenic mouse model systems to design most effective treatment strategies targeting LMW-E in TNBC. (3) Elucidate the mechanism of synergism between Roscovitine and chemotherapy or PARP inhibition in TNBC. (4) Phase I trial with dose expansion to determine maximum tolerated dose (MTD), response rate (RR) and biologic effects of CDK2 inhibition with roscovitine (Seliciclib) given prior to liposomal doxorubicin in patients with metastatic TNBC. Collectively, the successful completion of this grant will be a step toward providing patients with triple negative breast cancer a personalized approach to therapy, which has the potential of eradicating their disease.
The lack of specific targets for the triple negative breast cancer (TNBC) patients remains a major challenge for physicians and patients. We have identified a novel, druggable target for TNBC that can be used not only to identify those that would respond to targeted therapy, but also provide novel treatment strategy for this group of patients and has the potential of eradicating their disease.
|Pickering, Curtis R; Bast Jr, Robert C; Keyomarsi, Khandan (2015) How will we recruit, train, and retain physicians and scientists to conduct translational cancer research? Cancer 121:806-16|
|Caruso, J A; Akli, S; Pageon, L et al. (2015) The serine protease inhibitor elafin maintains normal growth control by opposing the mitogenic effects of neutrophil elastase. Oncogene 34:3556-67|
|Hunt, Kelly K; Wingate, Hannah; Yokota, Tomoya et al. (2013) Elafin, an inhibitor of elastase, is a prognostic indicator in breast cancer. Breast Cancer Res 15:R3|
|Duong, Mylinh T; Akli, Said; Macalou, Sira et al. (2013) Hbo1 is a cyclin E/CDK2 substrate that enriches breast cancer stem-like cells. Cancer Res 73:5556-68|
|Duong, MyLinh T; Akli, Said; Wei, Caimiao et al. (2012) LMW-E/CDK2 deregulates acinar morphogenesis, induces tumorigenesis, and associates with the activated b-Raf-ERK1/2-mTOR pathway in breast cancer patients. PLoS Genet 8:e1002538|
|Akli, Said; Van Pelt, Carolyn S; Bui, Tuyen et al. (2011) Cdk2 is required for breast cancer mediated by the low-molecular-weight isoform of cyclin E. Cancer Res 71:3377-86|