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Research at Mass General
Read the Miyamoto Lab 2017-2018 Annual Report
David T. Miyamoto, MD, PhDAssistant Professor of Radiation Oncology Harvard Medical SchoolMassachusetts General Hospital Cancer Center
The Miyamoto laboratory focuses on the discovery and development of novel biomarkers to guide the personalized treatment of patients with prostate and bladder cancer. We focus on two general classes of biomarkers, namely those based on the molecular profiles of tumor biopsies, and those based on circulating tumors cells (CTCs) in the blood that can be sampled non-invasively and repeatedly. By analyzing these patient-derived specimens, we have identified new molecular predictors of response to therapy and potential mechanisms of treatment resistance. Our overall aim is to develop tools for “real-time precision medicine” to probe the molecular signatures of cancers as they evolve over time, and to guide the precise and rational selection of appropriate therapies for each individual patient with prostate or bladder cancer.
David T. Miyamoto, MD, PhD Principal Investigator
The mission of our translational research laboratory is to develop biomarkers that inform clinical decisions in the management of patients with genitourinary malignancies. In prostate cancer, there is a critical unmet need for predictive biomarkers to guide therapy in settings ranging from localized to metastatic disease. For example, multiple therapeutic options are now available for metastatic castration-resistant prostate cancer (mCRPC) including androgen receptor (AR) targeted therapies, cytotoxic chemotherapy, and PARP inhibitors, but we lack non-invasive biomarkers that can reliably predict treatment responses and guide selection of the most appropriate therapy for each individual patient. In localized prostate cancer, there is an unmet need for molecular biomarkers to guide the rational selection of appropriate management options, which include active surveillance, radical prostatectomy, or radiation therapy with or without androgen deprivation therapy. Similarly, in bladder cancer, muscle-invasive bladder cancer can be treated with either radical cystectomy or bladder-sparing trimodality therapy (transurethral tumor resection followed by chemoradiation), but this decision is often made based on patient or physician preference. For each of these cases, there is an urgent need for biomarkers to guide patients towards the most appropriate therapy based on the biology of the tumor. Our laboratory is centered on discovering and developing such molecular biomarkers.
A major focus of our laboratory is the investigation of circulating biomarkers in cancer patients. Circulating tumors cells (CTCs) are rare cancer cells shed from primary and metastatic tumors into the peripheral blood, and represent a “liquid biopsy” that may be performed repeatedly and non-invasively to monitor treatment efficacy and study tumor evolution during therapy. In collaboration with a multidisciplinary team of bioengineers, molecular biologists, and clinicians at MGH, we have studied the application of novel microfluidic technologies to isolate and analyze CTCs from the blood of cancer patients. We have used CTC analyses to monitor therapy in patients with localized and metastatic prostate cancer, interrogate androgen receptor (AR) signaling status in patients undergoing treatment with AR-targeted therapies, and studied the significance of CTC clusters in the development of metastases. Through comprehensive single cell RNA-sequencing of prostate CTCs, we demonstrated that noncanonical Wnt signaling contributes to therapeutic resistancein mCRPC. Recently, we derived RNA signatures in CTCs that predict resistance toAR-targeted therapy in metastatic cancer and early dissemination of disease in localized cancer. Ongoing projects include the development of CTC molecular signatures to predict outcomes after PARP inhibitor therapy in mCRPC, after local therapy in localized prostate cancer, and after bladder-sparing trimodality therapy in patients with muscle-invasive bladder cancer.
A dividing circulating tumor cell isolated from a prostate cancer patient, immunostained for PSA (red), PSMA (orange), and DNA (blue), adjacent to a leukocyte immunostained for CD45 (green) and DNA (blue).
A second focus of the laboratory is the development of novel tissue-based biomarkers. We utilize technologies including microfluidic real-time PCR, next-generation sequencing, and branched chain RNA in situ hybridization (RNA-ISH) to evaluate molecular signatures in limited quantities of formalin-fixed paraffin-embedded (FFPE) tumor biopsy tissues. These molecular findings are correlated with clinical outcomes to identify novel biomarkers predictive of treatment response. We developed an RNA-ISH assay to detect the constitutively active androgen receptor mRNA splice variant AR-V7 in archival FFPE tissues, and demonstrated its prognostic value in patients with mCRPC. We recently identified immune and stromal molecular signatures predictive of outcomes after bladder-sparing chemoradiation therapy for bladder cancer. We are currently evaluating these and other candidate biomarkers as predictors of treatment response in prospective clinical trials and carefully defined retrospective clinical cohorts. Through these approaches, we aim to develop circulating and tissue-based biomarkers in a variety of clinical contexts, and develop and actualize the concept “real-time precision medicine”, integrating genomic analyses of liquid and tissue biopsies to guide the personalized care of patients with genitourinary malignancies.
Efstathiou JA, Mouw K, Gibb E, Liu Y, Wu CL, Drumm M, da Costa JB, du Plessis M, Wang NQ, Davicioni E, Feng FY, Seiler R, Black PC, Shipley WU, Miyamoto DT. Impact of immune and stromal infiltration on outcomes following bladder-sparing trimodality therapy for muscle-invasive bladder cancer. European Urology. 2018, in revision.
Miyamoto DT, Lee RJ, Kalinich M, LiCausi J, Zheng Y, Chen T, Milner JD, Emmons E, Ho U, Broderick K, Silva E, Javaid S, Kwan TT, Hong X, Dahl DM, McGovern FJ, Efstathiou JA, Smith MR, Sequist LV, Kapur R, Wu CL, Stott SL, Ting DT, Giobbie-Hurder A, Toner M, Maheswaran S, Haber DA. An RNA-based digital circulating tumor cell signature is predictive of drug response and early dissemination in prostate cancer. Cancer Discovery. 2018; 8:288-303.
Saylor PJ, Lee RJ, Arora KS, Deshpande V, Hu R, Olivier K, Meneely E, Rivera MN, Ting DT, Wu CL, Miyamoto DT. Branched chain RNA in situ hybridization for androgen receptor splice variant AR-V7 as a prognostic biomarker for metastatic castration-sensitive prostate cancer. Clinical Cancer Research. 2017; 23:363-369.
Zheng Y*, Miyamoto DT*, Wittner BS, Sullivan JP, Aceto N, Jordan NV, Yu M, Karabacak NM, Comaills V, Morris R, Desai R, Desai N, Emmons E, Lee RJ, Wu CL, Sequist LV, Haas W, Ting DT, Toner M, Ramaswamy S, Maheswaran S, Haber DA. Expression of ß-globin by cancer cells promotes cell survival during dissemination. Nature Communications. 2017; 8:14344.
Miyamoto DT, Zheng Y, Wittner BS, Lee RJ, Zhu H, Broderick KT, Desai R, Fox DB, Brannigan BW, Trautwein J, Arora KS, Desai N, Dahl DM, Sequist LV, Smith MR, Kapur R, Wu CL, Shioda T, Ramaswamy S, Ting DT, Toner M, Maheswaran S, Haber DA. RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance. Science. 2015; 349:1351-1356.
Miyamoto DT, Sequist LV, Lee RJ. Circulating Tumor Cells – Monitoring Treatment Response in Prostate Cancer. Nature Reviews Clinical Oncology. 2014; 11(7):401-12.
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