Ana deCarvalho
Department
Oncology and Pharmacology
Research Interests
- Brain tumor pre-clinical research
- Development of patient derived models
- Experimental therapeutics: mechanisms of resistance and target validation
- Tumor evolution and drivers of plasticity and stemness
Research Description
High grade glioma is the most prevalent and aggressive primary brain tumor in adults, characterized by poor prognosis and resistance to the standard of care, comprised of surgical resection and treatment with radiation and DNA-alkylating agents. The Hermelin Brain Tumor Center (HBTC) at Henry Ford Hospital in Detroit hosts one of the world's largest brain tumor biorepositories and was a major contributor to The Cancer Genome Atlas (TCGA). Leveraging this valuable resource, our research team has developed a panel of cancer stem-like cells derived from freshly resected high-grade gliomas, capturing the key genomic abnormalities typically observed in the clinic. These cells are used for in vitro studies and for establishing patient-derived orthotopic tumor xenografts in mice (PDX) to empower a pre-clinical program focused on addressing key challenges preventing better clinical outcomes for patients: molecular diversity among patients, co-activation of multiple oncogenic pathways, lack of predictive biomarkers, and tumor cell plasticity and evolution.
- We are currently evaluating the efficacy of investigational and clinically relevant compounds in patient-derived models while integrating treatment response data with comprehensive pre- and post-treatment molecular profiling to identify predictive biomarkers. By examining therapy-induced genomic and phenotypic alterations that drive resistance, we aim to propose and validate novel combination treatment strategies. These studies, conducted in clinically relevant models of high-grade glioma, are expected to enhance the design of future clinical trials and facilitate the stratification of patients for the most effective therapeutic approaches.
- In high-grade gliomas, focal genomic amplification is the most common mechanism of oncogene activation. Our recent research has revealed that these amplifications frequently occur on extrachromosomal DNA rather than within chromosomes—a phenomenon preserved in our patient-derived models (deCarvalho et al., Nature Genetics, 2018). This discovery has profound implications for tumor evolution and therapeutic response. Employing these models, we are investigating the therapeutic potential of targeting oncogenic drivers activated by extrachromosomal amplifications. Additionally, we are exploring an innovative strategy aimed at disrupting a key DNA repair pathway essential for the formation and maintenance of oncogenic amplicons.
- Furthermore, we are examining how aberrantly activated developmental programs contribute to tumor plasticity, heterogeneity, and a transient “cancer stem cell” phenotype that promotes drug resistance. Current studies focus on the roles of Sox2 and MET-activated pathways in these processes.
Recent Publications
Complete list of published work here.
Selected Publications
Berezovsky A, Nuga O, Datta I, Bergman K, Sabedot T, Gurdziel K, Irtenkauf S, Hasselbach L, Meng Y, Mueller C, Petricoin EF-III, Brown S, Purandare N, Aras S, Mikkelsen T, Poisson L, Noushmehr H, Ruden D, deCarvalho AC. Impact of Developmental State, p53 Status, and Interferon Signaling on Glioblastoma Cell Response to Radiation and Temozolomide Treatment (2025) PLoS ONE 20(2): e0315171. https://doi.org/10.1371/journal.pone.0315171
Malta TM, Sabedot TS, Morosini NS, Datta I, Garofano L, Vallentgoed WR, Varn FS, Aldape K, D'Angelo F, Bakas S, Barnholtz-Sloan JS, Gan HK, Hasanain M, Hau AC, Johnson KC, Cazacu S, deCarvalho AC, Khasraw M, Kocakavuk E, Kouwenhoven MCM, Migliozzi S, Niclou SP, Niers JM, Ormond DR, Paek SH, Reifenberger G, Sillevis Smitt PA, Smits M, Stead LF, van den Bent MJ, Van Meir EG, Walenkamp A, Weiss T, Weller M, Westerman BA, Ylstra B, Wesseling P, Lasorella A, French PJ, Poisson LM, Consortium TG, Verhaak RGW, Iavarone A, Noushmehr H. The epigenetic evolution of glioma is determined by the IDH1 mutation status and treatment regimen. (2024) Cancer Res. 84(5):741 – 756. PubMed PMID: 38117484.
Ye LF, Reznik E, Korn JM, Lin F, Yang G, Malesky K, Gao H, Loo A, Pagliarini R, Mikkelsen T, Lo DC, deCarvalho AC*, Stockwell BR (2020)*. Patient-derived glioblastoma cultures as a tool for small-molecule drug discovery. Oncotarget 11(4):443-451 (PMID 32064048) (*) co-corresponding authors.
Snyder J, Poisson LM, Noushmehr H, Castro AV, deCarvalho AC, Robin A, Mukherjee A, Lee I, Walbert T (2019). Clinical and research applications of a brain tumor tissue bank in the age of precision medicine. Personalized Medicine 16(2):145-156 (PMID 30816054)
deCarvalho AC, Kim H, Poisson LM, Winn ME, Mueller C, Cherba D, Koeman J, Seth A, Protopopov A, Felicella M, Zheng S, Multani A, Zhang Y, Zhang J, Nam DH, Petricoin EF, Chin L, Mikkelsen T, Verhaak RGW (2018). Discordant inheritance of chromosomal and extrachromosomal DNA elements contributes to dynamic disease evolution in glioblastoma. Nat Genet. 50 (5): 708 – 717 (PMID: 29686388)
Irtenkauf SM, Sobiechowski S, Hasselbach LA, Nelson KK, Transou AD, Carlton ET, Mikkelsen T, deCarvalho AC (2017) Optimization of glioblastoma mouse orthotopic xenograft models for translational research. Comparative Medicine 67(4):300-314. (PMID: 28513420)
Berezovsky AD, Poisson LM, Cherba D, Webb CP, Transou AD, Lemke NW, Hong X, Hasselbach LA, Irtenkauf SM, Mikkelsen T, deCarvalho AC. (2014) Sox2 promotes malignancy in glioblastoma by regulating plasticity and astrocytic differentiation. Neoplasia, 16(3):193-206 (PMID: 24726753) COVER ARTICLE