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.
|Caruso, Joseph A; Duong, Mylinh T; Carey, Jason P W et al. (2018) Low-Molecular-Weight Cyclin E in Human Cancer: Cellular Consequences and Opportunities for Targeted Therapies. Cancer Res 78:5481-5491|
|Carey, Jason P W; Karakas, Cansu; Bui, Tuyen et al. (2018) Synthetic Lethality of PARP Inhibitors in Combination with MYC Blockade Is Independent of BRCA Status in Triple-Negative Breast Cancer. Cancer Res 78:742-757|
|Chen, Xian; Low, Kwang-Huei; Alexander, Angela et al. (2018) Cyclin E Overexpression Sensitizes Triple-Negative Breast Cancer to Wee1 Kinase Inhibition. Clin Cancer Res 24:6594-6610|
|Francis, Ashleigh M; Alexander, Angela; Liu, Yanna et al. (2017) CDK4/6 Inhibitors Sensitize Rb-positive Sarcoma Cells to Wee1 Kinase Inhibition through Reversible Cell-Cycle Arrest. Mol Cancer Ther 16:1751-1764|
|Hunt, Kelly K; Karakas, Cansu; Ha, Min Jin et al. (2017) Cytoplasmic Cyclin E Predicts Recurrence in Patients with Breast Cancer. Clin Cancer Res 23:2991-3002|
|Doostan, Iman; Karakas, Cansu; Kohansal, Mehrnoosh et al. (2017) Cytoplasmic Cyclin E Mediates Resistance to Aromatase Inhibitors in Breast Cancer. Clin Cancer Res 23:7288-7300|
|Balaji, Kavitha; Vijayaraghavan, Smruthi; Diao, Lixia et al. (2017) AXL Inhibition Suppresses the DNA Damage Response and Sensitizes Cells to PARP Inhibition in Multiple Cancers. Mol Cancer Res 15:45-58|
|Nanos-Webb, A; Bui, T; Karakas, C et al. (2016) PKCiota promotes ovarian tumor progression through deregulation of cyclin E. Oncogene 35:2428-40|
|Jabbour-Leung, Natalie A; Chen, Xian; Bui, Tuyen et al. (2016) Sequential Combination Therapy of CDK Inhibition and Doxorubicin Is Synthetically Lethal in p53-Mutant Triple-Negative Breast Cancer. Mol Cancer Ther 15:593-607|
|Lucenay, Kimberly S; Doostan, Iman; Karakas, Cansu et al. (2016) Cyclin E Associates with the Lipogenic Enzyme ATP-Citrate Lyase to Enable Malignant Growth of Breast Cancer Cells. Cancer Res 76:2406-18|
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