Faculty
Cynthia Ma.jpg

Cynthia X. Ma, MD, PhD

Associate Professor
Department of Medicine
Oncology Division
Medical Oncology

Clinical Interests

  • Breast cancer

Research Interests

  • Pharmacogenomics of anticancer agents
  • Predictive biomarkers
  • Developmental therapeutics

Contact

  • 314-362-9383 (tel)
  • 314-362-7086 (fax)
  • 4515 McKinley Research Building, Room 3311 (office)
  • Division of Oncology
    Campus Box 8076
    Washington University Medical School
    660 South Euclid Avenue
    St. Louis, MO 63110

Research

Dr. Ma is a physician scientist with a research focus on pre-clinical and early phase clinical investigations in developing molecular therapeutics for breast cancer through collaborative research. Dr. Ma is leading several investigator-initiated trials with in genomic biomarker focused breast cancer populations, including the neoadjuvant AKT inhibitor trial in the PIK3CA mutant population, the neoadjuvant CDK4/6 inhibitor in the PIK3CA WT population and the trial of neratinib in metastatic HER2 non-amplified but mutant patient population.

In addition to clinical trial development, the Ma laboratory studies clinical specimens and patient-derived xenograft models to investigate biomarkers of responsiveness for targeted agents. One particular focus in the evaluation of the role of phosphatidylinositol 3-kinase (PI3K) pathway inhibitors in the treatment of triple negative breast cancer (TNBC: negative for the expression of estrogen receptor, progesterone receptor and HER2 gene amplification).

PI3K pathway signaling plays key regulatory roles in many cellular processes, including cell survival, proliferation, differentiation and angiogenesis (see Figure). Hyperactivation of the PI3K/AKT pathway has been associated with TNBC. A significantly higher level of Akt phosphorylation has been observed in TNBC patient specimens compared with non-TNBC cases. Loss of PTEN or INPP4B has been the most frequently implicated culprit for such activation in TNBC. In addition, increased levels of pAKT correlated with loss of PTEN protein and DNA copy number. The data regarding the importance of PTEN are consistent with observations of PTEN inactivation leading to "Basal-like" breast cancer in animal models. In the recent breast cancer TCGA (The Cancer Genome Atlas) report, PI3K pathway activity, either by gene expression signature or reverse phase protein array (RPPA) phosphoproteomic signature, was highest in basal-like breast cancer. Common PI3K pathway gene abnormalities identified in the TCGA TNBC data set included PIK3CA mutation (7%), Loss/mutations of PTEN (35%) and loss of INPP4B (16%), which were associated with increased PI3K pathway signaling activation. The high frequency of PI3K pathway activation in TNBC renders it an attractive therapeutic target. A phase 2 trial of BKM120 (a PI3K inhibitor) in patients with metastatic triple negative breast cancer is ongoing (ClinicalTrials.gov identifier: NCT01629615).

To evaluate the in vivo effect of PI3K pathway inhibition on TNBC, we tested the activity of MK-2206 (an AKT inhibitor) and MK-8669 (an mTOR inhibitor) in two patient-derived xenograft models of TNBC, both of which are negative for PTEN protein expression by immunohistochemistry (IHC) and have high levels of pAKT. A synergistic effect on tumor growth and cell proliferation was observed. Since loss of PTEN is the most frequent mechanism for PI3K pathway activation in TNBC, we evaluated the effect of PTEN loss on tumor cell sensitivity to PI3K pathway inhibition by stably knocking down PTEN in a patient-derived xenograft model of TNBC with normal PTEN and low pAKT at baseline. PTEN knockdown sensitized tumor response to PI3K pathway inhibition. These results indicated that a subpopulation of TNBC is growth dependent on PI3K pathway signaling. The laboratory is currently focused on experiments identifying the molecular predictors of response and mechanisms of resistance, through a Komen funded investigation using patient-derived xenograft models of TNBC. The goal is to develop biomarker directed clinical trials of novel therapeutic strategies in patients with TNBC.

 

PI3K Pathway

PI3K Pathway