Our Research
Research conducted with the Ellis Lab is currently funded by grants awarded from the National Cancer Institute (NCI/NIH), and the Prostate Cancer Foundation
Genetic/Epigenetic Drivers of Aggressive Variant Prostate Cancer and Lineage Plasticity
Prostate cancer (PCa) is the most common visceral malignancy in men. Prostate adenocarcinoma (PDAC) remains localized and indolent in most patients, but 15% of patients are diagnosed with metastatic disease at presentation. About 20-30% of patients receiving definitive treatment for local disease will recur with metastasis. Androgen deprivation therapy (ADT) has been the backbone for PCa treatment by inhibiting androgen receptor (AR) signaling. However, resistance to this therapy is inevitable and men will progress to castrate-resistant PCa (CRPC). Despite efforts to advance treatment options for CRPC patients, the average survival remains approximately 3 years. This identifies a current unmet need, for the discovery of more precise targeted therapies that provide durable responses in CRPC patients. To meet this challenge, we first need to understand the therapy resistance mechanisms driving the evolution of these lethal forms of PCa. A majority patients undergo disease progression via reactivation of AR signaling. However, it has been an increasingly accepted mechanism of resistance in approximately a quarter of tumors which involves a diminished tumor dependence on AR signaling, a term referred to as androgen indifferent, or aggressive variant prostate cancer (AVPC).
AVPC is associated with lineage plasticity, loss of luminal markers, and gain of stemness and neuroendocrine markers. Our recent findings highlighted that concurrent loss of the tumor suppressor genes – Retinblastoma-1 (RB1) and Phosphatase and Tensin Homolog (PTEN) in mouse models resulted in induction of prostate cancer demonstrating lineage plasticity associated with metastatic progression and therapeutic resistance. Our animal model findings significantly overlapped with human prostate cancer patient data. Key to these findings, was the deregulation of the epigenetic factor – Enhancer of Zeste Homolog-2 (EZH2). We demonstrated that by inhibiting the function of EZH2 that therapeutic resistance was reversed. These data involved key evidence for the role of RB1 and EZH2 in driving AVPC, and how this could be combated therapeutically to restore the tumor sensitivity to ADT.
Current Ongoing Projects:
Epigenetics and Immunity Underlying Prostate Cancer Initiation and Progression
Recently, the approval of immunotherapy has generated great excitement of the potential to induce the patient’s own immune system to fight their cancer. However, not all cancers are considered ‘immune hot’, meaning the patient will not likely respond to immunotherapy. This is especially relevant for prostate cancer. Our work involves delineating the molecular mechanisms governed by the tumor cells epigenetic machinery, and how therapeutic targeting of this machinery by epigenetic therapies can increase a tumors immunity (turning up the heat), and increase response to immunotherapy.
Forward Genetic Screens Involving Insertional Mutagenesis Mouse Models to Discover Genes Underlying Drivers of Aggressive Prostate Cancer and Therapeutic Resistance.
This work involves genetic additions onto the Hi-Myc GEMM of PCa generated. It is established that Myc is a bone fide driver of mouse and human PCa initiation and progression. However, Myc alone does not drive aggressive PCa in the mouse or select patients with aggressive PCa. This makes the Hi-Myc mouse an ideal platform for discovery of genes involved in PCa initiation and progression to aggressive PCa.
Our gene discovery approach will involve utilizing sleeping beauty mutagenesis. We have generated a PSACreERT2:PB-HiMyc:T2Onc3:SB11(floxed) GEMM for this purpose. Inducing sleeping beauty transposition exclusive to the mouse prostate will allow for the identification and validation of novel genetic drivers of PCa progression and therapeutic resistance.
Stepping Outside the Prostate Cancer Space:
Epigenetics and Immunity in Clear Cell Renal Cell Carcinoma (ccRCC)
Recently it was demonstrated that loss-of-function mutation in a gene named PBRM1 in ccRCC patients could be a strong biomarker for patients whose response to immunotherapy could be favorable. So, what about the ccRCC patients without this mutation? Our preliminary data, has identified a possible epigenetic mechanism that could be targeted to allow ccRCC patients without PBRM1 mutations to respond more favorably to immunotherapy. This work to aim to dissect these epigenetics mechanisms to understand our tumor immunity is controlled and if targeting these epigenetic mechanisms will increase therapeutic response to immunotherapy.
More than just Genetically Engineered Mouse Models:
Generation and Utility of Murine and Human Organoid Bio-Banks (Supporting all Projects).
Over the past few years the generation of 3D organoid cultures have become of extreme interest to the scientific community and my lab’s research direction. Organoids cultures have demonstrated genomic stability when compared to their tissue of generation, and significant reduction in costs when compared to generation and maintenance of PDX models.
Gene Discovery: Currently my lab has been focusing on the generation of multi-tissue organoid bio-banks. We have specifically focused on harvesting tissue from prostate, kidney, and in future expand to bladder. Generation of organoids is currently underway utilizing both sleeping beauty insertional mutagenesis and CRISPR/Cas9 transgenic mouse models. The purpose is to generate non-malignant (normal) organoids that will serve as independent genetic platforms to allow for the discovery of genes that drive cancer initiation, progression of aggressive phenotypes, and drug resistance. In conjunction, human normal and malignant tissue sites mentioned above will also be utilized to generate equivalent human organoid models. Human organoids can be used to analyze and nominate putative genetic drivers of aggressive disease progression and drug resistance. Overall, this will build a powerful 3D culture system that will allow for stringent cross-species analysis for rapid identification and validation of genetic drivers of aggressive and drug resistant phenotypes.
Companion pre-clinical therapeutics: In line with our use of organoids for gene discovery, preclinical therapeutic trials will be utilized. A primary goal is to generate a bank of organoids (patient avatars) with aggressive/metastatic disease. In the era of precision medicine, we can genomically compare original tissue sample with companion organoids. Identified therapeutic targets will be then validated using patient organoids. This approach will generate a rapid result as to the patient’s chance of response to a nominated therapy. Further, combination approaches will be trialed utilizing FDA approved standard of care treatments for that cancer, or other experimental targeted therapies based off generated genomic data. This approach hopes to generate and provide a more rapid companion diagnostic pipeline compared to similar approaches in PDX models and patient genomic testing from external sources (eg: OncoDx). Overall, this will result in supplying the patient with more rapid information about their cancer and advising patients on appropriate clinical trials they could be enrolled.
Genetic/Epigenetic Drivers of Aggressive Variant Prostate Cancer and Lineage Plasticity
Prostate cancer (PCa) is the most common visceral malignancy in men. Prostate adenocarcinoma (PDAC) remains localized and indolent in most patients, but 15% of patients are diagnosed with metastatic disease at presentation. About 20-30% of patients receiving definitive treatment for local disease will recur with metastasis. Androgen deprivation therapy (ADT) has been the backbone for PCa treatment by inhibiting androgen receptor (AR) signaling. However, resistance to this therapy is inevitable and men will progress to castrate-resistant PCa (CRPC). Despite efforts to advance treatment options for CRPC patients, the average survival remains approximately 3 years. This identifies a current unmet need, for the discovery of more precise targeted therapies that provide durable responses in CRPC patients. To meet this challenge, we first need to understand the therapy resistance mechanisms driving the evolution of these lethal forms of PCa. A majority patients undergo disease progression via reactivation of AR signaling. However, it has been an increasingly accepted mechanism of resistance in approximately a quarter of tumors which involves a diminished tumor dependence on AR signaling, a term referred to as androgen indifferent, or aggressive variant prostate cancer (AVPC).
AVPC is associated with lineage plasticity, loss of luminal markers, and gain of stemness and neuroendocrine markers. Our recent findings highlighted that concurrent loss of the tumor suppressor genes – Retinblastoma-1 (RB1) and Phosphatase and Tensin Homolog (PTEN) in mouse models resulted in induction of prostate cancer demonstrating lineage plasticity associated with metastatic progression and therapeutic resistance. Our animal model findings significantly overlapped with human prostate cancer patient data. Key to these findings, was the deregulation of the epigenetic factor – Enhancer of Zeste Homolog-2 (EZH2). We demonstrated that by inhibiting the function of EZH2 that therapeutic resistance was reversed. These data involved key evidence for the role of RB1 and EZH2 in driving AVPC, and how this could be combated therapeutically to restore the tumor sensitivity to ADT.
Current Ongoing Projects:
- Determining the chromatin landscape downstream of RB1 loss, and role of EZH2 as a master regulator of this process.
- Discovery of Master Regulator Transcription Networks driving AVPC either dependent of independent of RB1 loss.
- Initiating support data for first in human clinical trials of novel therapeutic directions for mCRPC patients (with an emphasis on the AVPC phenotype).
- Determining synthetic-lethal interactions in RB1 mutant prostate cancers.
Epigenetics and Immunity Underlying Prostate Cancer Initiation and Progression
Recently, the approval of immunotherapy has generated great excitement of the potential to induce the patient’s own immune system to fight their cancer. However, not all cancers are considered ‘immune hot’, meaning the patient will not likely respond to immunotherapy. This is especially relevant for prostate cancer. Our work involves delineating the molecular mechanisms governed by the tumor cells epigenetic machinery, and how therapeutic targeting of this machinery by epigenetic therapies can increase a tumors immunity (turning up the heat), and increase response to immunotherapy.
Forward Genetic Screens Involving Insertional Mutagenesis Mouse Models to Discover Genes Underlying Drivers of Aggressive Prostate Cancer and Therapeutic Resistance.
This work involves genetic additions onto the Hi-Myc GEMM of PCa generated. It is established that Myc is a bone fide driver of mouse and human PCa initiation and progression. However, Myc alone does not drive aggressive PCa in the mouse or select patients with aggressive PCa. This makes the Hi-Myc mouse an ideal platform for discovery of genes involved in PCa initiation and progression to aggressive PCa.
Our gene discovery approach will involve utilizing sleeping beauty mutagenesis. We have generated a PSACreERT2:PB-HiMyc:T2Onc3:SB11(floxed) GEMM for this purpose. Inducing sleeping beauty transposition exclusive to the mouse prostate will allow for the identification and validation of novel genetic drivers of PCa progression and therapeutic resistance.
Stepping Outside the Prostate Cancer Space:
Epigenetics and Immunity in Clear Cell Renal Cell Carcinoma (ccRCC)
Recently it was demonstrated that loss-of-function mutation in a gene named PBRM1 in ccRCC patients could be a strong biomarker for patients whose response to immunotherapy could be favorable. So, what about the ccRCC patients without this mutation? Our preliminary data, has identified a possible epigenetic mechanism that could be targeted to allow ccRCC patients without PBRM1 mutations to respond more favorably to immunotherapy. This work to aim to dissect these epigenetics mechanisms to understand our tumor immunity is controlled and if targeting these epigenetic mechanisms will increase therapeutic response to immunotherapy.
More than just Genetically Engineered Mouse Models:
Generation and Utility of Murine and Human Organoid Bio-Banks (Supporting all Projects).
Over the past few years the generation of 3D organoid cultures have become of extreme interest to the scientific community and my lab’s research direction. Organoids cultures have demonstrated genomic stability when compared to their tissue of generation, and significant reduction in costs when compared to generation and maintenance of PDX models.
Gene Discovery: Currently my lab has been focusing on the generation of multi-tissue organoid bio-banks. We have specifically focused on harvesting tissue from prostate, kidney, and in future expand to bladder. Generation of organoids is currently underway utilizing both sleeping beauty insertional mutagenesis and CRISPR/Cas9 transgenic mouse models. The purpose is to generate non-malignant (normal) organoids that will serve as independent genetic platforms to allow for the discovery of genes that drive cancer initiation, progression of aggressive phenotypes, and drug resistance. In conjunction, human normal and malignant tissue sites mentioned above will also be utilized to generate equivalent human organoid models. Human organoids can be used to analyze and nominate putative genetic drivers of aggressive disease progression and drug resistance. Overall, this will build a powerful 3D culture system that will allow for stringent cross-species analysis for rapid identification and validation of genetic drivers of aggressive and drug resistant phenotypes.
Companion pre-clinical therapeutics: In line with our use of organoids for gene discovery, preclinical therapeutic trials will be utilized. A primary goal is to generate a bank of organoids (patient avatars) with aggressive/metastatic disease. In the era of precision medicine, we can genomically compare original tissue sample with companion organoids. Identified therapeutic targets will be then validated using patient organoids. This approach will generate a rapid result as to the patient’s chance of response to a nominated therapy. Further, combination approaches will be trialed utilizing FDA approved standard of care treatments for that cancer, or other experimental targeted therapies based off generated genomic data. This approach hopes to generate and provide a more rapid companion diagnostic pipeline compared to similar approaches in PDX models and patient genomic testing from external sources (eg: OncoDx). Overall, this will result in supplying the patient with more rapid information about their cancer and advising patients on appropriate clinical trials they could be enrolled.