Ana C. deCarvalho, PhD.
Adjunct Assistant Professor
Departments of Oncology and Pharmacology
Wayne State University School of Medicine
Dept. of Neurosurgery
Henry Ford Hospital
Mentoring: Artem Berezovsky (Year 2)
- Clonal evolution, genomic heterogeneity, and response to therapy in tumors and patient-derived models of high grade glioma
- Mechanisms of resistance, target validation, and combination therapies for glioblastoma
- Developmental programs aberrantly activated in high grade gliomas as key drivers of plasticity, transient cancer stem cell phenotype and drug resistance
High grade astrocytomas are the most prevalent and aggressive central nervous system tumors in the adult population. Despite intensive treatment comprised of surgical resection, radiation and cytotoxic chemotherapy, prognosis is still unfavorable. Mechanisms of resistance to therapy include drug delivery to the brain, molecular diversity among tumors sharing the same histological grade, intratumoral heterogeneity, and lack of predictive biomarkers. The Hermelin Brain Tumor Center at Henry Ford Hospital has one of the largest brain tumor biorepositories in the world, and contributed significantly to The Cancer Genome Project (TCGA). My lab has leveraged this resource to create a panel of cancer stem-like cells from freshly resected high grade gliomas covering in depth the main genomic abnormalities encountered in the clinic. These cells are used for in vitro studies and also to establish patient-derived orthotopic tumor xenografts in mice (PDX).
Using these models, we are investigating how the developmental programs aberrantly activated in high grade gliomas drive plasticity and heterogeneity, leading to a transient "cancer stem cell" and phenotype, and contributing to drug resistance. Sox2 and MET-activated pathways are currently being studied.
To further validate the models, we are investigating the consequences of changes in selective pressure on neoplastic cells in the different microenvironments: from the original tumor, to dissociated cells in culture, and to the mouse brain. By employing exome sequencing, low pass whole genome sequencing, RNAseq, targeted proteomics and FISH, we access preservation of clonal driver genomic alterations, occurrence of clonal evolution, and changes in gene expression and signaling pathways. We are especially interested in the effect of the microenvironment on extrachromosomal DNA amplification.
The PDXs are enrolled in pre-clinical trials testing the anti-tumor efficacy of compounds in early development or already in clinical trials. The treatment efficacy results are integrated with pre-treatment molecular profiling to identify biomarkers of response. By studying how therapy-driven genomic and phenotypic alterations contribute to resistance, new combination therapies can be proposed and tested in the models. It is expected that the results of these studies with relevant models of high grade glioma will better inform future clinical trials, including the stratification of patients to the most appropriate therapies. We are currently focusing in particular on the molecular correlates of sensitivity of high grade gliomas to the inhibition of serine/threonine kinases mTOR and DNA-PK.
Wang Q, Hu B, Hu X, Kim H, Squatrito M, Scarpace L, deCarvalho AC, Lyu S, Li P, Li Y, Barthel F, Cho HJ, Lin YH, Satani N, Martinez-Ledesma E, Zheng S, Chang E, Sauvé CG, Olar A, Lan ZD, Finocchiaro G, Phillips JJ, Berger MS, Gabrusiewicz KR, Wang G, Eskilsson E, Hu J, Mikkelsen T, DePinho RA, Muller F, Heimberger AB, Sulman EP, Nam DH, Verhaak RGW. Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment. Cancer Cell. 2017;32:42-56.e6.
Yadav VN, Zamler D, Baker GJ, Kadiyala P, Erdreich-Epstein A, DeCarvalho AC, Mikkelsen T, Castro MG, Lowenstein PR. CXCR4 increases in-vivo glioma perivascular invasion, and reduces radiation induced apoptosis: A genetic knockdown study. Oncotarget. 2016;7:83701-19.
Quartararo CE, Reznik E, deCarvalho AC, Mikkelsen T, Stockwell BR. High-Throughput Screening of Patient-Derived Cultures Reveals Potential for Precision Medicine in Glioblastoma. ACS Med Chem Lett. 2015;6:948-52.
Giladi ND, Ziv-Av A, Lee HK, Finniss S, Cazacu S, Xiang C, Waldman Ben-Asher H, deCarvalho A, Mikkelsen T, Poisson L, Brodie C. RTVP-1 promotes mesenchymal transformation of glioma via a STAT-3/IL-6-dependent positive feedback loop. Oncotarget. 2015;6:22680-97.
PhD (2001), Florida State University, Tallahassee, FL