Beltran Lab - Precision Medicine and Prostate Cancer Research
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PictureEvaluation of metastatic biopsies of patients with metastatic prostate adenocarcinoma and NEPC identified molecular alterations enriched in NEPC
Neuroendocrine Prostate Cancer
Lineage plasticity has emerged as an important mechanism of treatment resistance in prostate cancer, which may manifest as low prostate specific antigen (PSA) progression, resistance to androgen receptor (AR) pathway inhibitors, and sometimes small cell neuroendocrine pathologic features (Beltran H et al). At present, there is no established therapies for patients developing lineage plasticity or neuroendocrine prostate cancer (NEPC). 

​Our laboratory is focused on understanding the biology underlying lineage plasticity that drives tumor evolution and therapy resistance. We have identified key genomic and epigenomic events that occur during NEPC progression (Beltran H et al), and we are exploring how the order of these events, tumor heterogeneity, and the pressures of AR-therapy influences plasticity and tumor aggressiveness. Our goal is to develop biomarker-driven clinical approaches for patients with NEPC through the initiation of early phase clinical trials. 

Epigenetic dysregulation underlying lineage plasticity. Epigenetic dysregulation is a key driver of lineage plasticity in prostate cancer including trans-differentiation of prostate adenocarcinoma to neuroendocrine prostate cancer (NEPC). EZH2, a component of the polycomb repressive complex 2 (PRC2), regulates the transcriptional repressive mark H3K27me3. Similar to controlling cell-fate determination during normal development, EZH2 can affect lineage state during prostate cancer progression. Several EZH2 inhibitors (EZH2i) are in clinical development; these trials are currently in biomarker-unselected populations. In work led by Dr. Balaji Venkadakrishnan in the Beltran lab, we are defining the lineage-specific action and differential activity of EZH2 in both prostate adenocarcinoma and neuroendocrine prostate cancer (NEPC) subtypes of advanced prostate cancer to better understand the role of EZH2 in modulating differentiation, lineage plasticity, and to identify mediators of response and resistance to EZH2 inhibitor therapy. Mechanistically, EZH2 modulates bivalent genes that results in upregulation of NEPC-associated transcriptional drivers (e.g., ASCL1) and neuronal gene programs in NEPC, and leads to forward differentiation after targeting EZH2 in NEPC (Venkadakrishnan et al). Subtype-specific downstream effects of EZH2 inhibition on cell cycle genes support the potential rationale for co-targeting cyclin/CDK to overcome resistance to EZH2 inhibition.  
 
Dysregulation of Notch signaling and therapeutic targeting of DLL3. We discovered expression of the notch inhibitory ligand delta like ligand 3 (DLL3) in the vast majority of NEPC and a subset of aggressive castration resistant adenocarcinoma (Puca et al). DLL3 is not expressed in localized prostate cancer or benign tissues. DLL3 is also expressed in small cell lung cancer (SCLC), another highly aggressive neuroendocrine carcinoma with limited therapeutic options. DLL3 represents a novel therapeutic target for both NEPC and SCLC. We have been studying a novel T cell engager that targets DLL3 both in preclinical models and in an early phase clinical trial. In work led by Dr Shengyu Ku in the Beltran Lab, we are focused on understanding mechanisms of response and resistance to DLL3-targeted therapies and exploring novel combination strategies. DLL3 is a notch inhibitory ligand, and we identified significant downregulation of the Notch pathway during prostate cancer progression from adenocarcinoma to neuroendocrine prostate cancer where it functions as a tumor suppressor (Ku et al). Activation of Notch in neuroendocrine and Rb1/Trp53-deficient prostate cancer models led to phenotypic conversion towards a more indolent non-neuroendocrine state with glandular features and expression of luminal lineage markers. This was accompanied by up-regulation of MHC and type I interferon and immune cell infiltration. These data support Notch signaling as a suppressor of neuroendocrine differentiation in advanced prostate cancer and provides insights into how Notch signaling influences lineage plasticity and the tumor microenvironment. In addition to targeting DLL3, we are also studying regulation of other cell surface targets in CRPC and NEPC including B7-H7 (Yamada et al) and PSMA (described below).
 
Anatomical and Cellular Determinants of Intrinsic and Acquired Resistance to PSMA-Targeted Therapy.
Prostate-specific membrane antigen (PSMA) has emerged as an important therapeutic target in metastatic castration-resistant prostate cancer (CRPC). However, not all patients respond to PSMA-targeted therapy, in part due to heterogeneity of tumor expression of the target PSMA (Bakht et al). Furthermore, loss of PSMA expression develops in up to 15-20% of patients with CRPC, and the underlying mechanisms remain poorly defined. Our Lab is studying PSMA regulation in metastatic CRPC and in the context of androgen receptor (AR)-positive and AR-negative disease. In PSMA-expressing CRPC patient tumors, as well as in a PSMA-positive orthotopic xenograft model of CRPC, we observed lower PSMA expression in liver lesions versus other sites of metastatic disease, suggesting a potential role of the microenvironment in modulating PSMA expression (Bakht et al). In work led by Martin Bakht in the Beltran Lab, we are delving deep into the mechanisms that underly PSMA heterogeneity and resistance to PSMA-RLT. We are using PSMA PET and FDG PET imaging and multi-omic (transcriptomic and metabolomic) profiling to study tumors that have developed resistance to PSMA-RLT in both patients and in preclinical models. How sites of metastases including the liver, and how different tumors can be PSMA-positive and PSMA-negative in the same patient, contribute to resistance to PSMA-RLT are being investigated. We aim to develop novel strategies to overcome treatment resistance and ultimately improve patient outcomes for patients treated with PSMA-RLT.

Organoid models
A major hurdle in the study of advanced prostate cancer and resistance mechanisms  is a lack of existing preclinical models. Our lab has generated and characterized tumor organoids derived from needle biopsies of metastatic lesions. We have demonstrated concordance of molecular features between organoids and their corresponding patient tumors. These organoids also develop metastatic disease when transplanted into animals as xenografts. We are utilizing these organoids and organoid xenografts to understand the biologic role of epigenetic modifiers and other emerging drivers of NEPC progression and metastasis. High-throughput organoid drug screening nominated single agents and drug combinations suggesting repurposing opportunities (Puca L et al).
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Patient derived organoids- immunofluorescence showing protein expression of NEPC markers
​Liquid Biopsies
Serial biopsies to look for NEPC transformation or other mechanisms of treatment resistance are not always feasible or safe for patients with advanced prostate cancer. We are developing liquid biopsy approaches including circulating tumor cells and circulating tumor DNA (genomics and methylation) to detect the emergence of resistance features non-invasively (Beltran et al; Franceschini et al). 
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Liquid biopsies to dissect intrapatient tumor heterogeneity
​​​​Precision Medicine
​Genomic profiling is widely used in cancer care to identify actionable alterations for individual patients within the context of precision medicine (Mateo et al; Ku et al). However, not all patients with sequencing performed receive a targeted therapy, due in part to accessibility to clinical trials as well as a still incomplete understanding regarding the clinical, biologic and functional impact of identified alterations. We are working across cancer types to interrogate the genetic and molecular landscape of cancer, including the integration of newer platforms, such as whole genome sequencing, RNA-seq, and DNA methylation, to understand the functional and clinical significance of both common and uncommon molecular alterations and to develop new and informed therapeutic approaches for patients. Through collaboration within a multidisciplinary team at DFCI spanning both the clinic and the lab, we are working to develop the next generation of biomarkers and targets to inform cancer care. 
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Integration of clinical and molecular patient features to guide precision cancer care
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©2022 Beltran Lab at Dana-Farber Cancer Institute
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