No targeted therapeutic strategies are currently available against triple-negative (TN) breast cancer, the most difficult-to-treat form of breast cancer, which does not overexpress human epidermal growth factor receptor 2 (HER2) and lacks the expression of the estrogen and progesterone receptors. Thus, there is an urgent need in deepening our understanding of this aggressive breast cancer subtype and identifying clinically relevant targets for therapeutic intervention. We have recently discovered that an oncogenic transcription factor MYC as well as the MYC-dependent signaling pathways are significantly up-regulated in primary human triple-negative breast tumors. In addition, we found that MYC activation is associated with patients? poor prognosis suggesting that the MYC pathways may play a fundamental role in driving the formation of these aggressive tumors. How can we kill MYC-driven TN tumors? Because MYC is a transcription factor, rationally designed small molecule inhibitors that can directly inhibit its activity are not available for clinical use An alternative approach in selectively killing MYC-driven tumors is to exploit the existence of """"""""synthetic-lethal"""""""" interactions. Our group previously took a cell cycle-biased approach and discovered that inhibition of the mitotic kinase cyclin-dependent kinase (CDK) 1 resulted in apoptosis in cells engineered to overexpress MYC. The mechanism of such cell death involved an up-regulation of a pro-apoptotic BCL-2 family member BIM. We subsequently used this approach to treat TN cell lines and xenograft tumors with elevated MYC expression. These observations suggest that MYC-dependent synthetic-lethal interactions exist, and importantly, can be targeted to selectively kill MYC-driven tumors.
Aim 1 of this proposed research will further study the clinical potential of small molecule CDK inhibition against MYC-driven TN cancers particularly in combination with clinical inhibitors of anti-apoptotic BCL-2 members. This is based on our novel hypothesis that, because CDK inhibition up-regulates BIM and activates mitochondrial intrinsic pathway, the combined use of the inhibitors for CDK and anti-apoptotic BCL-2 family members may significantly enhance the rate of cell death.
Aim 2 will characterize a newly discovered synthetic-lethal interaction between MYC activation and inhibition of Pim1, a non-essential, kinase previously shown to genetically interact with MYC.
Aim 3 will conduct a high-throughput small molecule screen to identify potential lead molecules capable of inducing MYC-dependent synthetic lethality in mammary cells. We will carry out these experiments using a combination of model human mammary epithelial cells, genetically defined cancer cell lines, and a panel of novel human-in-mouse orthotopic tumor grafts models. If successful, the proposed research will not only expand our knowledge on MYC biology but will also provide novel therapeutic concepts to be tested again patients with TN tumors.
This proposal will explore ways of better understanding and tackling triple-negative breast cancers, for which no targeted treatment strategies are currently available. We will combine model human mammary epithelial cells, a panel of human breast cancer cell lines, and novel human-in-mouse tumor graft mouse models to identify druggable proteins that can be inhibited to induce cell death specifically in MYC-driven triple-negative tumors. The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the Critique section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The Resume and Summary of Discussion section above summarizes the final opinions of the committee.
|Horiuchi, Dai; Camarda, Roman; Zhou, Alicia Y et al. (2016) PIM1 kinase inhibition as a targeted therapy against triple-negative breast tumors with elevated MYC expression. Nat Med 22:1321-1329|
|Martins, Maria M; Zhou, Alicia Y; Corella, Alexandra et al. (2015) Linking tumor mutations to drug responses via a quantitative chemical-genetic interaction map. Cancer Discov 5:154-67|
|Horiuchi, Dai; Anderton, Brittany; Goga, Andrei (2014) Taking on challenging targets: making MYC druggable. Am Soc Clin Oncol Educ Book :e497-502|
|Balko, Justin M; Giltnane, Jennifer M; Wang, Kai et al. (2014) Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets. Cancer Discov 4:232-45|