NCI Rising Scholars: Cancer Research Seminar Series (Upcoming Webinars)

Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome.
Erin M Parry, MD, PhD, K08 Awardee
Dana-Farber Cancer Institute

Dr. Parry received her undergraduate degree from Colby College and attended Johns Hopkins University School of Medicine where she earned an MD and a PhD. Upon graduation from medical school, Dr. Parry completed residency training in internal medicine at the Johns Hopkins Hospital followed by medical oncology fellowship at Dana-Farber/Partners Cancer Care. During her fellowship, Dr. Parry conducted post-doctoral research in the laboratory of Dr. Catherine Wu on Richter transformation of CLL. She is now an independent investigator at the Dana-Farber Cancer Institute in the Department of Hematologic Neoplasia and Instructor at Harvard Medical School. Dr. Parry's laboratory research currently focuses on the transformation of indolent B cell malignancies to aggressive lymphoma and mechanisms of immune evasion in lymphoma and CLL.

Richter syndrome (RS) evolving from chronic lymphocytic leukemia (CLL) exemplifies an aggressive malignancy that arises from an indolent or chronic cancer. Until recently, little was known about the molecular basis of this transformation from CLL to RS. To identify the genetic events that lead to the transformation of CLL to RS, we examined paired CLL and RS samples from a cohort of 52 patients with RS by whole exome sequencing and applied computational methods to separate out the RS and CLL DNA alterations. Our work uncovered recurrent genetic alterations in RS, including gene mutations, copy number alterations, whole genome doubling and chromothripsis, which was then confirmed in an independent validation cohort. We demonstrated that RS is largely different from DLBCL based on genetics, identified signaling pathways that are dysregulated in RS cells compared to CLL cells, and traced evolution to RS at a single-cell level. Our study identified genetic subtypes within RS and showed that RS DNA alterations can be detected in plasma samples, distinct from blood CLL cells, which may be a potential method for early diagnosis or detection of RS.

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Redlining-associated methylation in breast tumors: the impact of contemporary structural racism on the tumor epigenome
Jasmine M Miller-Kleinhenz, Ph.D., K99/R00 Awardee
Emory University

Jasmine Miller-Kleinhenz, PhD is an Assistant Professor at the University of Mississippi Medical Center. Dr. Miller-Kleinhenz conducts research at the intersection of molecular biology, epigenetics, and epidemiology to investigate the molecular underpinnings of health disparities. The goal of her research is to understand how socio-structural determinants of health “above the skin” influence biological mechanisms “under the skin” and drive cancer disparities. Her research currently focuses on investigating the impact of socio-structural determinants of health on the tumor epigenome as a potential driver of racial disparities in breast cancer. She is particularly interested in investigating the impact of aberrant epigenetic activation of stem cell signaling via exposure to disadvantageous social factors on the etiology of Triple Negative Breast Cancer. Employing her unique expertise in a combination of molecular assays, epigenetic techniques, and epidemiologic methodologies, her research aims to provide new insights into molecular mechanisms that contribute to breast cancer disparities.

As a growing number of studies reveal that racial and ethnic minorities are at an increased risk of developing and dying from various acute and chronic diseases, it is increasingly evident that research must be conducted that will reveal the molecular basis of health disparities. Health inequities often reflect social inequities and exploring the complex relationship between exposures to adverse social factors and their biological consequences is imperative. Our group has shown that place-based measures of structural racism (i.e. redlining) have been associated with an increase in breast cancer mortality. We hypothesized that exposure to adverse inequities may drive epigenetic perturbations that affect racial disparities in breast cancer outcomes. Here, I examined the association between contemporary redlining, a measure of structural racism at the neighborhood level, and DNA methylation in breast tumor tissue. My results showed that contemporary redlining is associated with differential methylation in 5 CpG sites. All genes are implicated in breast carcinogenesis, including genes related to inflammation, immune function, and stress response. Further exploration of the top 25 CpG sites, identified interaction of 2 sites by ER status and 1 site was associated with all-cause mortality. In addition, contemporary redlining is associated with epigenetic age acceleration and age acceleration is slightly associated with all-cause mortality. These results identify novel associations between contemporary redlining and the breast tumor DNA methylome. These data are the first to show that structural racism impacts the breast tumor epigenome and provide a strong foundation for further study into how socio-structural determinants “above the skin” influence biological mechanisms “under the skin” and drive disparities. This work will provide new molecular mechanistic insights governing breast cancer disparities and has broader implications for pharmacological treatments and policy interventions that would contribute to the ultimate goal of achieving health equity.

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Vascular endothelial profilin-1 drives a protumorigenic tumor microenvironment and tumor progression in renal cancer
Dave Gau, PhD, K99/R00 Awardee
University of Pittsburgh

Dr. David Gau is a Lecturer at the University of Pittsburgh, Department of Bioengineering. After earning his Bachelor’s in bioengineering at the University of Pittsburgh, David travelled to Armidale, Australia as a Whitaker Scholar before joining Partha Roy’s laboratory at Pitt for his Ph.D. Following his Ph.D., Dr. Gau continued to work with Dr. Roy for his postdoctoral research and worked on evaluating the role of myocardin-related transcription factor in cancer and his current work on the role of profilin-1 in renal cell carcinoma. Prior to receiving the K99/R00 transition award, David was supported by the National Cancer Center in his postdoctoral training and NSF GRFP in his PhD training. In addition to his research work, David has also earned a certificate in STEM teaching through CIRTL (Center for the Integration of Research, Teaching, and Learning) and micro-credential in leading people in organizations through the Katz Graduate School of Business.

Roughly 80,000 new cases of renal cell carcinoma (or kidney cancer) with estimated 15,000 deaths occur per year. Clear cell renal cell carcinoma is the most common subtype of renal cell carcinoma, accounting for over 75% of kidney cancer cases. Metastatic renal cell carcinoma patients also have a 5-year survival of less than 10% with median survival being around 13 months. A key characteristic of this type of tumor is its highly vascularized tumor microenvironment, meaning that the environment is rich in blood vessels. This is due to loss of a number of genes such as Von-Hippel Lindau, or VHL, which plays a major role in initiation as well as progression of this disease. Outside of surgical removal of the primary tumor, anti-angiogenic therapies such as those targeting VEGF to promote vascular normalization are the first line therapy for renal cell carcinoma patients. Almost all these patients, however, develop resistance and progression of drug-resistant disease. In our recent study, we explored the role of actin-binding protein profilin-1 in regulation of renal cell carcinoma. We show that profilin-1 expression is higher in advanced stage renal cell carcinoma and correlated to lower patient survival. In addition, we note that increased profilin-1 expression is found mainly in tumor-associated vascular endothelial cells (the cells lining blood vessels) in human clear cell renal cell carcinoma patients. We have demonstrated previously that profilin-1 is important for many fundamental cellular processes such as cell migration, proliferation, and angiogenesis (new blood vessel formation). This study shows for the first-time proof of direct causal relationship between vascular endothelial profilin-1 dysregulation, alternations in tumor microenvironment, and disease progression in kidney cancer. This work also further justifies targeting profilin-1 for therapeutic benefit in kidney cancer.

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Patient‐reported causes of distress predict disparities in time to evaluation and time to treatment after breast cancer diagnosis.
Oluwadamilola Fayanju, MD, MA, MPHS, FACS, K08 Awardee
University of Pennsylvania

Oluwadamilola “Lola” Fayanju, MD, MA, MPHS, FACS, is the Helen O. Dickens Presidential Associate Professor in the Perelman School of Medicine at the University of Pennsylvania and Chief of the Division of Breast Surgery for Penn Medicine. She is also Surgical Director of the Rena Rowan Breast Center in the Abramson Cancer Center, Director of Health Equity Innovation at the Penn Center for Cancer Care Innovation, and a Senior Fellow in the Leonard Davis Institute of Health Economics. Her research spans four areas: (1) addressing disparities and promoting equity in breast cancer presentation, guideline-concordant care, and outcome; (2) improving prognostication and treatment for biologically aggressive variants of breast cancer including inflammatory, lobular, and metaplastic carcinoma; (3) optimizing oncologic care through the collection and application of patient-reported outcomes (PROs) and data on social determinants of health (SDOH); and (4) elucidating the importance of race, ethnicity, and gender in the conduct of research and the promotion of a diverse healthcare and medical research workforce.

We examined whether the National Comprehensive Cancer Network Distress Thermometer (DT) and Problem List, a patient-reported outcome measure (PROM), could be used to identify levels and causes of distress among women presenting with breast cancer.
We identified women aged ≥18 years with stage 0-IV breast cancer who were diagnosed in a single health system between January 2014 and July 2016. The baseline visit was defined as the first postdiagnosis, pretreatment clinical evaluation. Regression models were used to examine associations between baseline DT score (0 = none to 10 = extreme) and types of stressors (emotional, familial, practical, physical, spiritual) after adjustment for race/ethnicity and other characteristics and to identify predictors of time to evaluation (TTE) and time to treatment (TTT).
A total of 1029 women were included (median baseline DT score = 4). Emotional, physical, and practical stressors were associated with distress (all P < .05). Black patients (n = 258) were >2.5x as likely to report no distress as Whites (n = 675; OR 2.72; 95% CI, 1.68-4.40; P < .001) despite reporting a similar number of stressors. Higher DT scores were associated with shorter TTE and TTT while being Black and having physical or practical stressors were associated with delays in both (all P < .05). Having physical or practical stressors particularly exacerbated delays in TTE and TTT, for Hispanic patients, who represented only a small proportion of our cohort but had the longest delays to evaluation (23 days) and treatment (71 days) of any group and some of the highest median self-reported distress levels.
Early psychosocial evaluation could potentially address delays in time to care and mitigate disparities for vulnerable patients through targeted and culturally responsive interventions for modifiable barriers to care.

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Immunotherapeutic Targeting and PET Imaging of DLL3 in Small-Cell Neuroendocrine Prostate Cancer.
Jonathan Chou, M.D., Ph.D., K08 Awardee
University of California, San Francisco

Jonathan is an Assistant Professor of Medicine in the Division of Hematology & Oncology at the University of California, San Francisco (UCSF) and attending physician in the UCSF Genitourinary Medical Oncology program and UCSF Helen Diller Family Comprehensive Cancer Center. His lab research focuses on developing strategies to enhance responses to surface protein targeting therapies, such as antibody-drug conjugates (ADCs), bispecific T cell engagers (BiTEs) and chimeric antigen receptor (CAR) T cells. In addition, Jonathan is interested in understanding resistance mechanisms to surface targeting therapies. Jonathan completed his MD/PhD, residency in Internal Medicine and fellowship in Medical Oncology at UCSF and joined the faculty at UCSF in 2022. Jonathan’s research is supported the Prostate Cancer Foundation (PCF), the Bladder Cancer Advocacy Network (BCAN), the UCSF Benioff Initiative for Prostate Cancer, the DOD Prostate Cancer Research Program and the NCI/NIH.

Surface protein targeting therapies, such as antibody-drug conjugates (ADCs), bispecific T cell engagers (BiTEs) and chimeric antigen receptor (CAR) T cells are an exciting emerging class of cancer therapies. In this talk, we will discuss how to harness these surface proteins to build effective therapeutic and imaging agents, and how to modulate their expression in cancer cells to improve targeting efficacy. Using DLL3 as an example target in small-cell/neuroendocrine prostate cancer (SCNC), we will demonstrate how AMG 757 (tarlatamab), a half-life extended BiTE immunotherapy, redirects CD3-positive T cells to kill DLL3-expressing patient-derived xenografts (PDX) models of SCNC and provide long-term, durable tumor control in mouse models. We will explore how heterogeneity of DLL3 expression impacts response to AMG 757 and provide data on how PET imaging agents may help us with patient selection, as these therapies enter into clinical trials. Finally, we will explore methods to prime tumors and enhance surface protein target expression, which can lead to improved tumor control.

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Ipilimumab plus decitabine for patients with MDS or AML in posttransplant or transplant-naïve settings.
Jacqueline S Garcia, M.D., K08 Awardee
Dana-Farber Cancer Institute

Dr. Jacqueline S. Garcia is an Assistant Professor of Medicine at Harvard Medical School. She is a clinical/translational investigator in the Adult Leukemia Program at the Dana-Farber Cancer Institute and an attending physician at the Brigham & Women’s Hospital. She graduated from University of Illinois at Chicago College of Medicine and completed her internship and residency training in Internal Medicine at the University of Chicago. She next completed Hematology and Oncology Fellowship training at Stanford University. She joined Dana-Farber in 2015. Dr. Garcia’s research focuses on the design and execution of scientifically based early phase clinical and proof-of-concept studies in advanced myeloid malignancies, including MDS, myelofibrosis and acute myeloid leukemia. Much of her research centers on identifying novel therapeutic opportunities to leverage the anti-apoptotic pathway in chemoresistant leukemia and to address or prevent post-transplant relapse in the context of investigator-initiated trials (IIT). She is a Principal Investigator for several clinical trials, including IIT, ETCTN/CTEP, and pharmaceutical studies. Her research has received support from the National Institutes of Health/National Cancer Institute, Leukemia and Lymphoma Society, and Conquer Cancer Foundation.

Recurrence of acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) after transplant has exceedingly poor outcome. In a prior study at our center, single agent CTLA-4 checkpoint inhibitor (ipilimumab) generated remissions in cases of AML with low disease burden at relapse with induction of graft-versus-host disease. We asked if we could augment the rate of remission with combination decitabine plus ipilimumab in patients regardless of disease burden and if the alloreactive environment generated after transplant was required for response. In the context of a phase 1 multi-site clinical trial supported by the NCI/ETCTN, we enrolled and treated 48 patients with decitabine/ipilimumab in cohorts separated by transplantation status to assess for safety and preliminary efficacy. We also collected blood/bone marrow from each patient at the same time points before, on-therapy and at time of relapse when relevant to study the local and systemic tumor immune infiltrates. We discovered that immune-related adverse events were frequent and manageable in most patients, the recommended phase 2 dose was the same regardless of transplant status, and we identified responders in both cohorts. Multiplex immunofluorescence (MIF) analyses of paired sequential bone marrows revealed increases in CD4+ T cells after ipilimumab, but we did not consistently observe increases in activated CD8+ T cells among responders. Immune monitoring using Cytof revealed increases in T regulatory cells after ipilimumab but no correlation with response. Transcriptome-based analyses and MIF revealed differences in AML patients with leukemia cutis (skin) compared to those with marrow involvement, including infiltration of memory T cells and higher expression of CTLA-4 and FOXP3. Altogether, detailed immune and molecular correlatives identified potential mechanisms of response and resistance to combination therapy in advanced MDS/AML patients.

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An integrated isothermal nucleic acid amplification test to detect HPV16 and HPV18 DNA in resource-limited settings.
Kathryn A Kundrod, Ph.D., NCI Cancer Research Training Awardee
National Cancer Institute

Kathryn Kundrod, PhD, MPH is a Cancer Prevention Fellow at the National Cancer Institute (NCI), where she is focused on increasing access to cervical cancer screening with Dr. Philip Castle in the Clinical Genetics Branch of the Division of Cancer Epidemiology and Genetics. Through her fellowship, Dr. Kundrod is currently on rotation with the White House Office of Science and Technology Policy (OSTP), where serves as Senior Advisor for Cancer Moonshot Policy Coordination. Prior to joining NCI, Dr. Kundrod completed a PhD and postdoctoral fellowship in bioengineering at Rice University. During her training, she developed point-of-care HPV tests for early cervical cancer detection in resource-limited settings, as well as a COVID-19 saliva test for use in a surveillance laboratory that she managed. Dr. Kundrod earned a Master of Public Health (MPH) degree from the Harvard T.H. Chan School of Public Health during her Cancer Prevention Fellowship.

Globally, there is an urgent need for low-cost and accessible cervical cancer screening tests. The most sensitive method of cervical cancer screening is testing for high-risk human papillomavirus (HPV) DNA, but current HPV DNA tests are not widely available in resource-limited settings, where the burden of cervical cancer is highest. This talk will outline the recent development of a prototype test that detects two types of HPV DNA – HPV16 and HPV18 – to help meet the need for low-cost cervical cancer screening. The developed test is low-cost, manufacturable, and point-of-care-friendly, enabled by two technologies, isothermal amplification and lateral flow detection, that reduce the cost and complexity of the test. Moreover, the test requires six user steps, produces a result in 45 minutes, and can be performed using small benchtop instruments. In field testing in low- and high-resource settings, the developed test yielded a clinically relevant limit of detection of 1,000 HPV16 or HPV18 DNA copies. Taken together, these results demonstrate the feasibility of an integrated point-of-care HPV DNA test. With the inclusion of additional high-risk HPV types, this test has the potential to meet the need for a point-of-care cervical cancer screening test in resource-limited settings.

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Barriers and facilitators of Hispanic/Latino parents caregiving for a childhood cancer survivor: a qualitative study.
Carol Y Ochoa, Ph.D., M.P.H., K00 Awardee
University of California, San Diego

Dr. Carol Ochoa-Dominguez is a Postdoctoral fellow at the University of California San Diego in the Department of Radiation Medicine and Applied Sciences and a Member in Training of the Cancer Control Program at Moores Cancer Center. She is a cancer health disparities researcher; broadly, her research experience has centered on three areas of focus: 1) cancer survivors, 2) informal caregivers, and 3) cancer screening. Within this work, she uses a mixed-method approach to explore whether there are any racial/ethnic differences, the role of social determinants, and specific cultural factors that may be related to these outcomes.
Dr. Ochoa-Dominguez completed her doctoral degree in 2022 from the Department of Population and Public Health Sciences at the University of Southern California, where she was funded by the National Cancer Institute’s T-32 and F99/K00 awards. Before starting her doctorate training, she served as the Cancer Survivorship workgroup ORISE Fellow from 2016-2017 within the Division of Cancer Prevention and Control at the CDC. She also received her MPH in Behavioral Science and Health Education from the Rollins School of Public Health at Emory University in 2016 and her BA from UCLA in 2013.

We extend previous research on Hispanic/Latino caregiver experiences by exploring in-depth the perceived barriers and facilitators of parents in a safety-net clinic who are the primary caregivers throughout their child’s cancer journey. While there have been studies published on Hispanic/Latino caregivers of older adults, there has been little published on identifying the barriers and facilitators of caregiving experiences of parents. Given the intersecting complexities of this safety-net children’s clinic in Los Angeles, which serves primarily Hispanic, recently immigrated, Spanish-speaking, and Medicaid population, it is important to assess whether this vulnerable population has unique barriers and facilitators from previously published literature. Semi-structured phone interviews were conducted among 15 Hispanic/Latino parents caring for their child who was diagnosed with cancer. All interviews were conducted in English or Spanish based on the participant’s language preference. The interviews were recorded using a digital audio device and transcribed by a bilingual professional transcription service. To conserve the meaning of the interviews, they were transcribed and analyzed in the language in which they were conducted. Two bilingual coders independently reviewed transcripts coded them following reflexive thematic analysis and using elements of grounded theory methodology on Dedoose. This study revealed that multilevel factors impact Hispanic/Latino parents’ cancer care management. At the individual level, the magnitude of the caregiving responsibility acted as a barrier, while parents' self-described “relationship with God” acted as a facilitator. Interpersonal relationships, including familial flexibility and fluid roles in relation to caregiving and a positive relationship with the medical care team, were facilitators for caregivers. However, others' perceptions or misconceptions of their child’s illness were a barrier to caregiving. At the organizational and policy level, external financial resources and assistance navigating the application process were beneficial for parents. While issues related to financial hardship and uncertain immigration and citizenship status resulted in caregiver distress and challenges navigating the healthcare system. These findings can guide recommendations to address caregiver burden for this at-risk population at various levels, including suggestions for the healthcare system and policy level.

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