Current SPORE projects are described below. The grant also funds four Career Enhancement Projects and five Development Research Projects. Five previous CEPs and four previous DRPs have been funded since the SPORE grant was awarded to DF/HCC. Annual requests for proposals are issued for additional CEP & DRPs, usually in the spring. Notice of upcoming RFAs will be provided here.
Androgens, androgen receptor signaling and breast carcinogenesis.
- Aim 1: Evaluate the role of androgen and AR signaling in breast cancer risk in the NHS.
- Aim 2: Evaluate the role of androgens and AR signaling on breast cancer prognosis in the NHS.
- Aim 3: Use breast cancer subtype specific AR-target gene sets to confirm AR signaling as a predictor of prognosis in ER+ and ER-/HER2+ breast cancer in BIG-198 and NeoAlto.
Overcoming Resistance to HER2-Directed Therapies for Breast Cancer.
Aim 1: To use genetically engineered mouse (GEM) models to evaluate PI3K-targeted treatment strategies for HER2+ breast cancer
- Aim 1A: To compare the effects of p110 isoform-specific and pan-PI3K inhibitors in conjunction with HER2-directed therapy in GEM models of HER2 driven breast tumors.
- Aim 1B: To examine the response to HER2- and PI3K-targeted combination therapies of HER2 tumors with concomitant PIK3CA mutations or PTEN loss.
Aim 2: To identify and test resistance mechanisms to HER2- and PI3K-targeted therapies in GEM models
- Aim 2A: To test the ability of recently identified mechanisms of resistance to PI3K inhibitors to block response to combinations of HER2 and PI3K targeted therapies
- Aim 2B: To identify genes capable of conferring resistance to HER2-targeted inhibition in a GEM model
Aim 3: To evaluate the role of PI3K inhibition in conjunction with HER2-targeted therapy in patients with HER2+ breast cancer
- Aim 3A: To test the hypothesis that the addition of a PI3K inhibitor overcomes resistance to preoperative pertuzumab/trastuzumab based therapy
- Aim 3B: To identify PI3K-dependent and PI3K-independent resistance pathways enriched in residual tumors after preoperative HER2- and PI3K-directed therapy
- Aim 3C: To assess PI3K-dependent and PI3K-independent pathways associated with resistance to HER2- and/or PI3K-directed therapies in human breast cancer specimens
Novel Strategies to extend DNA Repair Therapies for Triple Negative Breast Cancer.
The overarching goal of the project is to utilize novel strategies to disrupt homologous recombination (HR) repair in BRCA-proficient triple-negative breast cancers (TNBC) in order to sensitize them to poly (ADP-ribose) polymerase (PARP) inhibition. The Project includes preclinical work in TNBC cell lines and patient-derived (PDX) models with ultimate translation to clinical trial.
- Aim 1: Evaluate the combination of a CDK1 inhibitor (dinaciclib) and a PARP inhibitor (veliparib/ABT-888) in the treatment of BRCA-proficient Triple Negative Breast Cancer
- Aim 2: Evaluate the combination of a PI3K inhibitor (BYL719) and a PARP inhibitor (olaparib) in the treatment of BRCA-proficient Triple Negative Breast Cancer (see modifications of original aims described below).
BET bromodomain proteins as novel therapeutic targets in Triple Negative Breast Cancer.
Aim 1: To define and characterize the drug target and downstream targets of JQ1/BET bromodomain inhibitors in TNBCs.
- Aim 1A: To identify key mediators of JQ1’s effects in TNBCs by global tagged-compound-binding assays (Chem-seq).
- Aim 1B: To analyze the gene expression profiles of TNBCs following JQ1/BET bromodomain inhibitor treatment and after downregulation of BRD4 or other relevant bromodomain proteins.
- Aim 1C: To perform ChIP-seq for BRD4 or other relevant bromodomain proteins in TNBC to identify JQ1/BET bromodomain inhibitor genomic targets.
- Aim 1D: To integrate analysis of all genomic data to define major downstream mediators of response to JQ1/BET bromodomain inhibitors in TNBCs.
Aim 2: To conduct a clinical trial to test JQ1/ BET bromodomain inhibitors in TNBC patients.
- Aim 2A: To conduct a phase II trial of JQ1/BET bromodomain inhibitors in patients with metastatic TNBC. The primary objective of the trial is to detect a signal of response to a bromodomain inhibitor in metastatic TNBC. Baseline, on treatment, and post-progression (in responding patients) tumor biopsies will be performed to facilitate mechanistic studies and the development of pharmacodynamic biomarkers and biomarkers predictive of clinical response.
- Aim 2B: To analyze the expression of the targets of JQ1/BET bromodomain inhibitors in primary human breast tumor samples. We will analyze the expression of direct drug targets, critical downstream effectors, and predictors of response identified in Aim 1 by immunohistochemistry and multi-color immunofluorescence.
- Aim 2C: To derive xenograft models from biopsies of patients enrolled in the clinical trial. These will be used to test hypotheses regarding biomarkers, targets, resistance mechanisms, and combination therapies.
Aim 3: To develop cell lines resistant to bromodomain inhibitors and characterize combination therapies to improve therapeutic responses and overcome acquired.
- Aim 3A: To develop resistant cell lines. We will start with sensitive TNBC cell lines and develop resistant derivatives by prolonged growth in gradually increasing JQ1 concentrations in cell culture or xenograft-bearing mice.
- Aim 3B: To investigate whether combining G2/M arrest inducing-drugs or targeted agents effective in TNBC with JQ1/BET bromodomain inhibitors leads to more efficient pre-clinical therapeutic responses.
Jeselsohn R, Buchwalter G, De Angelis C, Brown M, Schiff R. ESR1 mutations—a mechanism for acquired endocrine resistance in breast cancer. Nat Rev Clin Oncol. 2015;12(10):573-83. PMCID: PMC4911210.
Wang J, Zhang X, Beck AH, Collins LC, Chen WY, Tamimi RM, Hazra A, Brown M, Rosner B, Hankinson SE. Alcohol Consumption and Risk of Breast Cancer by Tumor Receptor Expression. Horm Cancer. 2015;6(5-6):237-46. PMCID: PMC4631632.
Costa C, Ebi H, Martini M, Beausoleil SA, Faber AC, Jakubik CT, Huang A, Wang Y, Nishtala M, Hall B, Rikova K, Zhao J, Hirsch E, Benes CH, Engelman JA. Measurement of PIP3 levels reveals an unexpected role for p110β in early adaptive responses to p110α-specific inhibitors in luminal breast cancer. Cancer Cell. 2015;27(1):97-108. PMCID: PMC4745884.
Goel S, Wang Q, Watt AC, Tolaney SM, Dillon DA, Li W, Ramm S, Palmer AC, Yuzugullu H, Varadan V, Tuck D, Harris LN, Wong KK, Liu XS, Sicinski P, Winer EP, Krop IE, Zhao JJ. Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors. Cancer Cell. 2016;29(3):255–69. PMCID: PMC4794996.
Cheng H, Liu P, Ohlson C, Xu E, Symonds L, Isabella A, Muller WJ, Lin NU, Krop IE, Roberts TM, Winer EP, Arteaga CL, Zhao JJ. PIK3CA(H1047R)- and Her2-initiated mammary tumors escape PI3K dependency by compensatory activation of MEK-ERK signaling. Oncogene. 2016;35(23):2961-70. PMCID: PMC4896860.
Wang Q, Liu P, Spangle JM, Von T, Roberts TM, Lin NU, Krop IE, Winer EP, Zhao JJ. PI3K-p110α mediates resistance to HER2-targeted therapy in HER2+, PTEN-deficient breast cancers. Oncogene. 2016;35(27):3607-12. PMCID: PMC4846581.
Ni J, Ramkissoon SH, Xie S, Goel S, Stover DG, Guo H, Luu V, Marco E, Ramkissoon LA, Kang YJ, Hayashi M, Nguyen QD, Ligon AH, Du R, Claus EB, Alexander BM, Yuan GC, Wang ZC, Iglehart JD, Krop IE, Roberts TM, Winer EP, Lin NU, Ligon KL, Zhao JJ. Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases. Nat Med. 2016;22(7):723-6. PMCID: PMC4938731.
Goel S, DeCristo MJ, Watt AC, BrinJones H, Sceneay J, Li BB, Khan N, Ubellacker JM, Xie S, Metzger-Filho O, Hoog J, Ellis MJ, Ma CX, Ramm S, Krop IE, Winer EP, Roberts TM, Kim HJ, McAllister SS, Zhao JJ. CDK4/6 inhibition triggers anti-tumour immunity. Nature. 2017;548(7668):471-5. PMCID: PMC5570667.
Johnson N, Johnson SF, Yao W, Li YC, Choi YE, Bernhardy AJ, Wang Y, Capelletti M, Sarosiek KA, Moreau LA, Chowdhury D, Wickramanayake A, Harrell MI, Liu JF, D’Andrea AD, Miron A, Swisher EM, Shapiro GI. Stabilization of mutant BRCA1 protein confers PARP inhibitor and platinum resistance. Proc Natl Acad Sci U S A. 2013;110(42):17041-6. PMCID: 3801063.
Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D’Andrea AD. Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov. 2015;5(11):1137-54. PMCID: PMC4631624.
Juvekar A, Hu H, Yadegarynia S, Lyssiotis CA, Ullas S, Lien EC, Bellinger G, Son J, Hok RC, Seth P, Daly MB, Kim B, Scully R, Asara JM, Cantley LC, Wulf GM. Phosphoinositide 3-kinase inhibitors induce DNA damage through nucleoside depletion. Proc Natl Acad Sci U S A. 2016;113(30):E4338-47. PMCID: PMC4968752.
Johnson SF, Cruz C, Greifenberg AK, Dust S, Stover DG, Chi D, Primack B, Cao S, Bernhardy AJ, Coulson R, Lazaro JB, Kochupurakkal B, Sun H, Unitt C, Moreau LA, Sarosiek KA, Scaltriti M, Juric D, Baselga J, Richardson AL, Rodig SJ, D'Andrea AD, Balmana J, Johnson N, Geyer M, Serra V, Lim E, Shapiro GI. CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer. Cell Rep. 2016;17(9):2367-81. PMCID: PMC5176643.
Matulonis UA, Wulf GM, Barry WT, Birrer M, Westin SN, Farooq S, Bell-McGuinn KM, Obermayer E, Whalen C, Spagnoletti T, Luo W, Liu H, Hok RC, Aghajanian C, Solit DB, Mills GB, Taylor BS, Won H, Berger MF, Palakurthi S, Liu J, Cantley LC, Winer E. Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer. Ann Oncol. 2017;28(3):512-8. PMID: 29773796.
Shapiro GI, Do KT, Tolaney SM, Hilton JF, Cleary JM, Wolanski A, Beardslee B, Hassinger F, Bhushan K, Cai D, Downey E, Pruitt-Thompson S, Barry SM, Kochupurakkal B, Geradts J, Unitt C, D'Andrea AD, Muzikansky A, Piekarz R, Doyle LA, Supko J. Phase 1 dose-escalation study of the CDK inhibitor dinaciclib in combination with the PARP inhibitor veliparib in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res. 2017;77(13 Suppl):Abstract nr C0147.
Konstantinopoulos PA, Barry WT, Birrer M, Westin SN, Farooq S, Cadoo K, Whalen C, Luo W, Liu H, Aghajanian C, Solit DB, Mills GB, Taylor BS, Won H, Berger MF, Palakurthi S, Liu JF, Cantley LC, Kaufmann SH, Swisher EM, D'Andrea AD, Winer E, Wulf GM, Matulonis UA. Phase 1 study of the alpha-specific PI3 kinase inhibitor BYL719 and the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib in recurrent ovarian and breast cancer: analysis of the dose escalation and ovarian cancer expansion cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACRS; Cancer Res. 2017;77(13 Suppl):Abstract nr CT008.
Almendro V, Cheng YK, Randles A, Itzkovitz S, Marusyk A, Ametller E, Gonzalez-Farre X, Munoz M, Russnes HG, Helland Å, Rye IH, Borresen-Dale A-L, Maruyama R, van Oudenaarden A, Dowsett M, Jones RL, Reis-Filho J, Gascon P, Gönen M, Michor F, Polyak K. Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of genetic and phenotypic cellular diversity. Cell Rep. 2014;6(3):514-27. PMCID: PMC3928845.
Almendro V, Kim HJ, Cheng Y-K, Gönen M, Itzkovitz S, Argani P, van Oudenaarden A, Sukumar S, Michor F, Polyak K. Genetic and phenotypic diversity in breast tumor metastases. Cancer Res. 2014;74(5):1338-48. PMCID: PMC3963810.
Janiszewska M, Liu L, Almendro V, Kuang Y, Paweletz C, Sakr RA, Weigelt B, Hanker AB, Chandarlapaty S, King TA, Reis-Filho JS, Arteaga CL, Park SY, Michor F, Polyak K. In situ single-cell analysis identifies heterogeneity for PIK3CA mutation and HER2 amplification in HER2-positive breast cancer. Nature Genet. 2015;47(10):1212-9. PMCID: PMC4589505.
Shu S, Lin CY, He HH, Witwicki R, Tabassum DP, Roberts JM, Janiszewska M, Huh SJ, Liang Y, Ryan J, Doherty E, Mohammed H, Guo H, Stover DG, Ekram MB, Peluffo G, Brown J, D’Santos C, Krop IE, Dillon D, McKeown M, Ott C, Qi J, Ni M, Rao PK, Duarte M, Wu S-Y, Chiang CM, Anders L, Young RA, Winer EP, Letai A., Barry WT, Carroll JS, Long HW, Brown M, Liu XS, Meyer CA, Bradner JE, Polyak K. Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer. Nature. 2016;529(7586):413-7. PMCID: PMC4854653.
Shu S, Polyak K. BET Bromodomain Proteins as Cancer Therapeutic Targets. Cold Spring Harb Symp Quant Biol. 2016;81:123-9. PMID:28062533.
Huh SJ, Oh H, Peterson MA, Almendro V, Hu R, Bowden M, Lis RL, Cotter M, Loda M, Barry WT, Polyak K, Tamimi RM. The proliferative activity of mammary epithelial cells in normal tissue predicts breast cancer risk in premenopausal women. Cancer Res. 2016;76(7):1926-34. PMCID: PMC4873436.
Marusyk A, Tabassum DP, Janiszewska M, Place AE, Trinh A, Rozhok AI, Pyne S, Guerrierro JL, Shu S, Ekram M, Ishkin A, Cahill DP, Nikolsky Y, Chan TA, Rimawi MF, Hilsenbeck S, Schiff R, Kent C. Osborne KC, Letai A, Polyak K. Spatial proximity to fibroblasts impacts molecular features and therapeutic sensitivity of breast cancer cells influencing clinical outcomes. Cancer Res. 2016;76(22):6495-6506. PMCID: PMC5344673.
Gil Del Alcazar CR, Huh SJ, Ekram MB, Trinh A, Liu LL, Beca F, Zi X, Kwak M, Bergholtz H, Su Y, Ding L, Russnes HG, Richardson AL, Babski K, Min Hui Kim E, McDonnell C, Wagner J, Rowberry R, Freeman GJ, Dillon D, Sorlie T, Coussens LM, Garber JE, Fan R, Bobolis K, Allred DC, Jeong J, Park SY, Michor F, Polyak K. Immune escape in breast cancer during in situ to invasive carcinoma transition. Cancer Discov. 2017 Jun 26. [Epub ahead of print]. doi: 10.1158/2159-8290.CD-17-0222. PMID:28652380.