Posted March 9, 2022
Two major efforts for the Kidney Cancer Research Program (KCRP) are to attract and develop promising early-career investigators (ECIs) and to facilitate collaboration to truly accelerate advances in the field. In fiscal year 2019 (FY19), with these goals in mind, the KCRP launched the Academy of Kidney Cancer Investigators (AKCI), bringing together talented ECIs, under the guidance of an Academy Dean, in a highly collaborative and intense mentorship program to foster the future thought leaders in kidney cancer research.
The Academy Dean – Brian Rini, M.D., Vanderbilt University
In FY19, Dr. Rini received the AKCI Dean Award to establish and lead the Academy through its first 5 years. With more than 20 years of experience in clinical and translational kidney cancer research and substantial mentorship credentials, Dr. Rini is well-positioned to understand the needs of ECIs. He identified five essential components as being fundamental to the success of the Academy: (1) commitment, of both the ECI and their Designated Mentor to the pursuit of impact-driven careers in the kidney cancer field; (2) the development of specific, measureable, achievable, relevant, and time-bound goals (SMART Goals) to keep the ECIs focused; (3) extensive networking, facilitated by the Academy, to help the ECIs gain exposure in the kidney cancer research community; (4) systematic feedback from the Academy’s members to the ECIs to facilitate achieving individual SMART Goals; and (5) establishing enhanced collaboration between the ECIs and the multidisciplinary kidney cancer research community.
To help ensure these five drivers of ECI success are continuously addressed, Dr. Rini established the AKCI Advisory Board, consisting of six preeminent kidney cancer investigators with diverse and complementary skill sets. The AKCI Advisory Board includes geographic, gender, seniority, and diversity of expertise that will provide the ECI and Designated Mentor pairs with an enhanced spectrum of resources, visibility, and opportunity for career advancement. The Board is comprised of the Chair, Dr. James Brugarolas (University of Texas Southwestern), Dr. Laurence Albieges (Gustave Roussy Institute), Dr. Sumanta Kumar Pal (City of Hope), Dr. David F. McDermott (Beth Israel Deaconess Medical Center), Dr. Marie (Celeste) Simon (University of Pennsylvania, and Dr. Robert G. Uzzo (Fox Chase Cancer Center).
FY19 ECIs – ECIs receive funding to perform specific research projects over the course of 4 years, while also participating in the dynamic mentoring environment established by the Academy Dean. The KCRP made three initial awards to ECIs during the FY19 funding cycle to represent the inaugural class of the Academy.
Understanding CD8+ T-Cell Specificity and Function in Renal Cell Carcinoma
David Braun, M.D., Ph.D., Yale School of Medicine (formerly Dana-Farber Cancer Institute)
Dr. Braun, who has been co-mentored by Dr. Toni Chouieri (Dana-Farber Cancer Institute), Dr. Catherine Wu (Dana-Farber Cancer Institute), and Dr. Marcus Bosenberg (Yale School of Medicine) is currently working to develop an improved understanding of how the immune system effectively responds to renal cell carcinoma (RCC), and how this relates to how a tumor might respond or become resistant to immunotherapy. His project will systematically identify unique molecular targets within RCC, so-called tumor antigens, which may serve as critical components to engage the immune system (CD8+ T cells) that infiltrates the tumor microenvironment. Additionally, Dr. Braun will define the specific antigens commonly recognized by tumor-resident T cells through an analysis of T cell receptor (TCR) clonality from patient tumor samples. Armed with these two important pieces of information, he will evaluate tumor biopsies from patients undergoing immune checkpoint inhibition therapy to determine if specific tumor antigens and/or TCRs are associated with improved patient outcomes. If ultimately successful, this work will provide information on which patients may derive the most benefit from immune checkpoint inhibition, and explain why others harbor tumors that do not respond. Additionally, this project may also illuminate possible new targets, against which future immune-based therapies can be developed and rapidly advanced into new clinical trials.
Exploiting Epigenetic Dysregulation to Identify Targetable Vulnerabilities in ccRCC
Abhishek Chakraborty, Ph.D., Cleveland Clinic Foundation
Dr. Chakraborty is intent on establishing a sustainable and kidney cancer-focused independent research career, and his research is centered on discovering novel and druggable targets in the most prevalent form of kidney cancer, clear cell RCC (ccRCC). The hallmark genetic lesion that defines ccRCC is the loss of the tumor suppressor, pVHL. Although this knowledge has delivered therapeutic options; advanced ccRCC remains ultimately incurable, establishing the need for more broadly effective and durable treatments for patients with the disease. Dr. Chakraborty has identified a novel gene, SLC1A1, as being more highly expressed in tumors lacking pVHL relative to tumors with functional pVHL such as in papillary or chromophobe RCC cases, which tend to be much less aggressive. SLC1A1 encodes the protein EAAT3, which was noted to increase with ccRCC disease stage; was capable of promoting growth in poorly tumorigenic cells with functional pVHL; and, shutting off EAAT3 decreased the growth of ccRCC cells, all of which suggests that it operates as an oncogene. Dr. Chakraborty, guided by his mentors, Dr. David McDermott (Beth Israel Deaconess Medical Center) and Dr. Nima Sharifi (Cleveland Clinic Foundation), has proposed to understand how chemical modification of SLC1A1 DNA is brought about by the loss of pVHL during ccRCC initiation and progression. Further work will evaluate how EAAT3 functions, biochemically, to enhance/alter ccRCC cellular metabolism to support the nutritional needs of kidney cancer cells. Though still early in the process, the projected outcomes from these studies could lay a foundation for targeting the chemical modification of SLC1A1, and potentially the protein it codes for, EAAT3, as potential new therapeutic options for patients with ccRCC.
Epigenetic Modifications of Cytosines in Clear Cell Kidney Carcinogenesis and Survival
Lucas Salas, M.D., Ph.D., Dartmouth College
Working to understand features that distinguish aggressive, lethal ccRCC from less aggressive tumors, Dr. Salas aims to establish a lengthy career tackling the problem of kidney cancer. Under the dual mentorship of Dr. James Brugarolas (University of Texas Southwestern Medical Center) and Dr. Brock Christensen (Dartmouth College), Dr. Salas is interested in exploring the role that hydroxymethylation of DNA plays in ccRCC biology and disease progression. Hydroxymethylation is one of the epigenetic modifications of the genome at cytosine residues (“C” base pair) – a chemical modification of DNA – rather than a mutation or deletion of a gene. Epigenetic modifications alter the expression of the genes (how your genome translates information into RNA and proteins) without altering the DNA sequence. Dr. Salas’ preliminary data suggests that hydroxymethylation, in general, is decreased in ccRCC samples compared to normal kidney tissues, and differs from other cytosine modifications in their locations, suggesting that the feature may contribute some information to action against the disease and, potentially, future therapies. The overall goals of his KCRP award are to fully characterize the state of hydroxymethylation patterns from 200 ccRCC and 50 normal kidney tissue samples. Additionally, Dr. Salas intends to correlate specific changes and patterns of hydroxymethylation with overall ccRCC survival rates. Finally, the project will seek out particular biomolecules whose presence is altered by changes to hydroxymethylation to determine their specific impact on ccRCC. If successful, this project could provide new understandings of ccRCC biology, opening the door for targeted therapies and/or insights into patient tumors, which may help guide decisions in the clinic.
FY20 ECIs – The KCRP was pleased to be able to bring an additional three new ECIs into the Academy during FY20 to join the inaugural class.
Evaluating HLA Class II Evolutionary Divergence as an Immunotherapy-Specific Kidney Cancer Biomarker
Ritesh Kotecha, M.D., Memorial Sloan Kettering Cancer Center
Dr. Kotecha’s career goals are to “improve the treatment and medical care for patients with advanced kidney cancers through the development of biomarker-directed strategies and novel therapeutics.” Having assembled a mentorship team consisting of Dr. Robert Motzer and Dr. Ari Hakimi (Memorial Sloan Kettering Cancer Center), Dr. Kotecha has proposed to study the potential of human leukocyte antigen (HLA) subtyping and genetic diversity as a biomarker to predict patient response to immunotherapy. HLA proteins are generally categorized into Class I and II, and are important in presenting tumor neoantigens, or biomolecules unique to tumor cells, to the host immune system to recognize as unnatural, attack, and remove. Recently, HLA Class I diversity has been shown to be associated with patient response to immunotherapy. In this project, Dr. Kotecha has proposed to evaluate the type and diversity of the HLA Class II proteins, as well as kidney cancer specific tumor neoantigens uniquely presented by the HLA proteins, as predictive indicators of patient response to immunotherapy. The anticipated results from the proposed study have high potential to be rapidly translated into clinical practice, as HLA subtyping is already routinely performed for patients in need of organ transplants to find donor matches. The establishment of a reliable biomarker to predict response to immunotherapy, prior to treatment, would impact treatment decision, helping to ensure more favorable outcomes in kidney cancer.
Overriding Radiation Therapy Resistance and Enhancing the Abscopal Effect in Renal Cancer
Krishnendu Pal, Ph.D., Mayo Clinic and Foundation, Jacksonville
The “abscopal effect” suggests that the use of ionizing radiation to treat primary tumors has a secondary clinical benefit of sensitizing metastatic tumors to an activated immune response. However, RCC is notoriously resistant to radiation therapy. Dr. Pal has previously demonstrated that targeted delivery of the chemotherapeutics, everolimus and YM155 (EY-L), inhibits tumor growth in mice, and separately sensitizes kidney cancer cells to radiation in the laboratory. With the mentorship of Dr. Debabrata Mukhopadhyay (Mayo Clinic and Foundation, Jacksonville), Dr. Pal proposes to evaluate how combining EY-L with radiation might act synergistically to treat primary RCC in several mouse models. Initially, studies will be performed in mice lacking an immune response to determine if EY-L can sensitize RCC xenografts to radiation in the body. These studies will then be extended by introducing a syngeneic mouse RCC tumor model to mice with a functioning immune system to begin to explore how EY-L and radiation of the primary tumor may also function to induce an abscopal effect, reducing or eliminating detectable metastatic lesions by activation of the immune system. Finally, Dr. Pal will explore these therapeutic modalities in the presence of Interleukin-2 (IL-2) treatment, which has been shown to promote an immune-response in the tumor microenvironment, potentially boosting the effectiveness of treatment at both the primary tumor, and metastatic lesions via enhanced abscopal effect. If successful, these results would provide preclinical evidence that RCC can be sensitized to radiotherapy with an added benefit of metastatic reduction, affording additional frontline treatment options that could be translated into early clinical trials.
Systemic Characterization of Kidney Cancer Tumor Suppressors in Modulating Metastasis and Response to Immunotherapy
Amrita Mangalvedhekar, Ph.D., Memorial Sloan Kettering Cancer Center
Dr. Mangalvedhekar, working with the mentorship of Dr. Emily Cheng (Memorial Sloan Kettering Cancer Center), seeks to identify the genetic changes within advanced ccRCC that promote metastasis and therapeutic resistance. Primary ccRCC frequently results from genetic loss of the VHL tumor suppressor gene but can be characterized in a large cohort of cases by loss of PBRM1, also a tumor suppressor gene, which may augment tumor responsiveness to immunotherapy. Dr. Mangalvedhekar has established a unique mouse model in which both VHL and PBRM1 have been deleted, and found that these mice develop multiple primary ccRCC-like lesions in their kidneys – yet do not develop metastatic disease. These findings suggest that additional genes must be involved in the progression of ccRCC to advanced metastatic states. Dr. Mangalvedhekar proposed to generate a mouse cell line from these mice tumors, to systematically inactivate a list of approximately 50 tumor suppressor genes, already known to be affected in human metastatic ccRCC. Cells with inactivated genes will be grafted in the mouse to surveil for genes whose loss promotes the development of metastatic lesions. Similarly, a second screen of nearly 600 potential tumor suppressor genes will be undertaken to determine if their loss modifies the response to immunotherapy in the primary tumors. The information generated by Dr. Mangalvedhekar’s proposed study has the potential to dramatically improve our understanding of the genetics behind ccRCC progression and response to current therapy, providing opportunity for new avenues of intervention.
Last updated Thursday, May 26, 2022