Career Enhancement Program
Awarded in 2016
Harnessing tumor associated macrophages for breast cancer therapy
Investigator: Jennifer Guerriero, PhD (DFCI)
- Aim 1: Test the hypothesis that TMP195 treatment enhances hormone and monoclonal antibody therapy in the MMTV-PyMT mouse model of breast cancer. Test the hypothesis that TMP195 treatment will enhance anti-estrogen therapy in the MMTV-PyMT mouse model of breast cancer. Test the hypothesis that TMP195 treatment will enhance anti-HER-2/neu monoclonal antibody therapy in the MMTV-PyMT mouse model of breast cancer.
- Aim 2: Test the hypothesis that TMP195-activated TAMs will benefit patients with triple negative breast cancer. Test the hypothesis that TMP195 induces tumor regression in a mouse model of triple negative breast cancer. Test the hypothesis that TMP195 will enhance PARP inhibitor therapy in a mouse model of triple negative breast cancer.
Breast cancer subtype specific risk prediction models to inform precision medicineapproaches to prevention and early detection
Investigator: Anne Marie McCarthy, PhD (MGH)
Existing breast cancer risk models do not consider tumor subtype and have limited predictive ability. Improving risk prediction models to estimate subtype specific risk using epidemiological, clinical, and imaging features could enable prediction of aggressive tumors and be used to guide more intensive prevention and screening strategies for women at high risk for poor prognosis cancers.
- Aim 1: Examine the relationship of epidemiologic risk factors and imaging features (e.g. breast density, mass characteristics, calcifications, asymmetry, architectural distortions) with aggressive breast cancer subtypes (TNBC, HER2+) among women undergoing routine screening mammography.
- Aim 2: Adapt existing breast cancer risk prediction models to generate subtype specific risk estimates.
Etiology and prevention of breast and ovarian cancers
Investigator: Megan Rice, ScD (MGH)
Breast cancer is the most commonly diagnosed cancer among US women and is the leading cause of cancer death for women
- Aim 1: Investigate the association between lifestyle factors related to inflammation, specifically sedentary behavior and a pro-inflammatory diet pattern, and risk of breast cancer diagnosed ≤10 years after childbirth. Secondarily, we will compare the strength of association between these factors and total breast cancer risk stratified by parity and time since childbirth in premenopausal women (i.e., nulliparous, ≤10 years, >10 years).
- Aim 2: Assess the relationship between aspirin and non-aspirin NSAIDs use and risk of breast cancer diagnosed ≤10 years after childbirth. Secondarily, we will compare the strength of the association between NSAIDs use and total breast cancer risk stratified by parity and time since childbirth in premenopausal women.
- Aim 3: Compare the expression of inflammation pathway markers in breast tumor tissue from women diagnosed ≤10 years since childbirth to tissue from those diagnosed >10 years since childbirth or to nulliparous women.
Awarded in 2015
Minority Supplement Award
Investigator: Shawn Johnson, PhD (DFCI)
The goal of this project was to further characterize the ability of CDK12 inhibition to sensitize triple negative breast cancer (TNBC) models, both BRCA-wildtype and –mutated, to PARP inhibitors.
- Aim 1: Further elucidate the structural mechanism by which dinaciclib, a pan-CDK inhibitor, inhibits CDK12 with greater efficacy than other known CDK9 inhibitors.
- Aim 2: Improve in vivo pharmacodynamic assays for assessing homologous recombination (HR) in FFPE-samples. Specifically, the quantification of RAD51 foci induction in FFPE-samples from patient derived xenografts (PDX) models.
- Aim 3: Develop and characterize novel covalent CDK12 inhibitors in collaboration with the Nathaneal Grey lab.
- Aim 4: Finalize and submit manuscript detailing combined CDK12/PARP inhibitor combination preclinical work.
Awarded in 2014
Integrative Subtype-Specific Prognostic Models for Precision Breast Cancer Diagnostics
Investigator: Andrew H Beck, MD, PhD (BIDMC)
We hypothesize that the expression of molecular signatures and morphologic phenotypes drive breast cancer progression in a subtype-specific manner. To discover morphologic phenotypes associated with breast cancer progression, we developed the Computational Pathologist (C-Path) system. To identify robust molecular signatures associated with breast cancer progression, we developed Significance Analysis of Prognostic Signatures (SAPS). In the current project, we will integrate the unique strengths of these methods and apply them to a large and well-annotated collection of breast cancer samples to build robust, biologically informative, data-driven tools for precision breast cancer diagnostics. The goal of this project is to identify morphological and molecular biomarkers of invasive breast cancer (IBC) prognosis in breast cancer molecular subtypes and to construct integrative subtype-specific prognostic models.
- Aim 1: To discover morphologic biomarkers associated with patient prognosis in breast cancer molecular subtypes.
- Aim 2: To validate subtype-specific prognostic expression biomarkers in breast cancer molecular subtypes.
- Aim 3: To build integrative subtype-specific prognostic models comprised of morphologic phenotypes, expression biomarkers, and host lifestyle factors to predict survival in breast cancer molecular subtypes.
Estrogen receptor mutations: the functional roles in endocrine resistance and potential as a therapeutic target
Investigator: Rinath Jeselsohn, MD (DFCI)
The estrogen receptor is a nuclear transcription factor that drives proliferation and growth of luminal type breast cancers and is the major target of hormone-based therapies for breast cancer. We have identified ESR1 mutations in up to 20% of metastatic endocrine resistant tumor samples. These mutations are all clustered in the ligand-binding domain and our functional studies indicate that these mutations confer constitutive activity and relative resistance to endocrine treatments.
- Aim 1: Establish stable cell lines and patient derived xenografts harboring the ESR1 mutations and determine the functional roles of the ER mutations in tumor growth, invasiveness, metastasis and endocrine resistance.
- Aim 2: Decipher the molecular mechanisms mediating the phenotype of the ESR1 mutations.
- Aim 3: Test the efficacy of estrogen receptor degraders combined with PI3K, CDK4/6 or HSP90 inhibitors to inhibit ESR1 mutational driven tumor growth in pre-clinical models.
Sapacitabine and Seleciclib in BRCA-Deficient Breast Cancer
Investigator: Sara Tolaney MD, MPH (DFCI)
The specific aims of our proposal focus on assessing homologous recombination (HR) proficiency in clinical samples of BRCA carrier patients enrolled to the sapacitabine/seliciclib combination trial. Enrollment to this cohort has not yet begun, so we have not been able to begin work on either of the specific aims to date.
- Aim 1: Assess HR proficiency of tumor samples using the Myriad Genetics HR-deficiency (HRD) assay
- Aim 2: Perform whole exome sequencing to determine the mutational signature of tumor samples
Assessing methods to improve the efficacy of PI3K inhibitors in PIK3CA mutated breast cancers
Investigator: Sadhna Vora, MD (MGH)
The goal of this project is to improve the efficacy of PI3K inhibitors (PI3Ki) in breast cancers driven by the oncogenic mutation of the PIK3CA gene. Our preliminary data suggested that either mTORi or CDKi, when combined with PI3Ki, could overcome resistance to single agent PI3Ki. Our work over the first year of the grant term has focused more on CDK/PI3Ki than mTOR/PI3Ki due to findings from the clinic of toxicities associated with the mTOR/PI3Ki combination (notably hyperglycemia and gastrointestinal issues).
- Aim 1: In vivo studies of PI3K inhibition with either mTORC or CDK 4/6 inhibitors to determine which treatment strategy is a more effective initial PI3Ki based therapy.
- Aim 2: Perform pooled shRNA screen on de novo resistant established and patient derived PIK3CA cell lines.
- Aim 3: to assess patient samples for biomarkers of resistance to PI3K inhibitors.
Identifying resistance mechanisms in ER+ breast cancer by translational genomics
Investigator: Nikhil Wagle, MD (DFCI)
The goal of this research is to apply both comprehensive genomic profiling and systematic functional approaches to test the hypothesis that somatic genetic differences may contribute to endocrine-resistance in breast cancer.
- Aim 1: to conduct a near-genome scale lentiviral open reading frame (ORF) screen for genes whose overexpression is sufficient to confer resistance to anti-estrogen therapy in breast cancer cell lines.
- Aim 2: To perform comprehensive genomic characterization of pre-treatment and post-progression breast cancer samples obtained from patients who have developed resistance to hormonal therapy.
Career Enhancement Project Publications
Vora SR, Juric D, Kim N, Mino-Kenudson M, Huynh T, Costa C, Lockerman EL, Pollack SF, Liu M, Li X, Lehar J, Wiesmann M, Wartmann M, Chen Y, Cao ZA, Pinzon-Ortiz M, Kim S, Schlegel R, Huang A, Engelman JA. CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell. 2014 Jul 14;26(1):136-49.
Dong F, Irshad H, Oh EY, Lerwill MF, Brachtel EF, Jones NC, Knoblauch NW, Montaser-Kouhsari L, Johnson NB, Rao LK, Faulkner-Jones B, Wilbur DC, Schnitt SJ, Beck AH. Computational pathology to discriminate benign from malignant intraductal proliferations of the breast. PLoS One. 2014 Dec ;9(12):e114885.
Oh EY, Christensen SM, Ghanta S, Jeong JC, Bucur O, Glass B, Montaser-Kouhsari L, Knoblauch NW, Bertos N, Saleh SM, Haibe-Kains B, Park M, Beck AH. Extensive rewiring of epithelial-stromal co-expression networks in breast cancer. Genome Biol. 2015 Jun 19;16:128.
Jeselsohn R, Buchwalter G, Angelis CD, Brown M, Schiff R. ESR1 mutations—a mechanism for acquired endocrine resistance in breast cancer. Nat Rev Clin Oncol. 2015 Oct;12 (10):573-83.
Irshad H, Montaser-Kouhsari L, Waltz G, Bucur O, Nowak JA, Dong F, Knoblauch NW, Beck AH. Crowdsourcing image annotation for nucleus detection and segmentation in computational pathology: evaluating experts, automated methods, and the crowd. Pac Symp Biocomput. 2015;294-305.
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, Balmaña 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 Nov 22;17(9):2367-2381.