Searching For & Finding Cancers' Achilles Heels
The Eighth Annual DCI Scientific Retreat Was One for the Books
The Duke Cancer Institute 8th Annual Scientific Retreat, held on December 3, 2021, attracted a broad array of faculty, trainees (students, residents, fellows, postdocs, etc.) and staff.
For a second year, the retreat was entirely virtual and there were no poster presentations owing to the ongoing Covid-19 pandemic.
“Hopefully, this will be the last time that we have to do it this way,” said executive director of DCI, Michael Kastan, MD, PhD, welcoming participants over Zoom.
That it was virtual didn't stop a series of lively discussions from moving full-steam ahead on a full Friday afternoon on topics such as DCI cancer health equity and engagement strategies, viral lymphomas, bone loss as a CLL co-morbidity, ways around immune system evasion, cardio-protective cancer therapy, new approaches for treating head and neck squamous cell carcinoma, clues as to how cystic lesions progress to pancreatic cancer, unlocking immune dysfunction in glioblastoma, cholesterol-control drugs and cancer, and the PARP revolution.
“We have a very full agenda today with great science from Duke trainees and faculty and are also celebrating several different anniversaries. First, it's my 10th anniversary as director of the Duke Cancer Institute and I have to say it's been a real privilege of my life to be in this role and to be able to work with such extraordinary people here. And I couldn't be more proud of everything that all the staff and all the faculty have done during the time that I've been here," said Kastan. "We're also celebrating the 50th anniversary of the National Cancer Act, which was signed in 1971, and put us down the path to NCI-designated cancer centers. The Duke Comprehensive Cancer Center (now DCI) was one of the original eight."
Kastan also noted that DCI's own 50th was on the horizon.
"This year we begin celebrating our 50th anniversary. We've made a tremendous impact on cancer research and patient care in the U.S. and around the world.”
And Then There Were Seven
Seven trainees — one from each of DCI's seven National Cancer Institute-designated DCI Research Programs — were selected by program leaders and the scientific review committee to present their research at the retreat. (This past fall, DCI Trainee Members were invited to submit, for oral-presentation consideration, an abstract on their research project).
Seven of these trainees received a $1,000 award from the DCI and the trainee with the most innovative basic-science research project, as is customary at the annual scientific retreat, received the Robert and Barbara Bell Basic Science Cancer Research Award in the amount of $5,000. Each trainee was introduced by either their mentor or a research program faculty leader and following their presentation took questions from their peers and DCI faculty via the Zoom chat feature,
“I want to do a special shout out to Dr. Robert Bell and Barbara Bell for sponsoring the Bell Award through a generous donation that they've made that allows us to identify the top scientific abstracts at each retreat. For those of you who don't know Bob, he was chair of the Cancer Biology Department here for many years. We’re so grateful to have them as such great supporters of the DCI,” said Kastan.
Emmanuela Bonglack, a 5th year PhD candidate in the Department of Pharmacology & Cancer Biology, was this year's recipient of the Bell Award for her basic-science abstract: "Targeting viral lymphomas through lactate export-associated metabolic vulnerabilities.” With research interests at the intersection of infectious disease, cancer biology, and pharmacology, she studies viral infections that can cause cancer with the hope of eventually applying what she's learned to the development of novel therapeutics.
Her project — the top submission in the DCI Cancer Biology Research Program category — zeroed in on the mechanisms through which, and the conditions under which, the Epstein–Barr virus (EBV) promotes B-cell lymphomas in immune-suppressed individuals. EBV is a ubiquitous herpes virus that infects more than 90% of the world's population, but most individuals with the virus are asymptomatic.
Bonglack is a member of the Luftig Lab where she's mentored by DCI virologist Micah A. Luftig, PhD, an associate professor of Molecular Genetics and Microbiology and Medicine and director of the Duke Center for Virology. Luftig has been nationally recognized for his work on EBV & cancer and this area is his lab's central focus.
Introducing Bonglack at the Scientific Retreat, Luftig said, “Emma is a really highly accomplished student already at this stage. She's recently published the work she’ll be presenting and was the recipient of an NCI F31 pre-doctoral fellowship award to extend her work into mouse models. She's also participating in Duke Scholars in Molecular Medicine to really learn and observe translation of research into clinical practice. It’s a great honor to have her recognized this year with the Bell Award.”
Born in Cameroon and raised there until she moved at the age of 12 to the U.S. with her family, Bonglack's work was als recently spotlighted by Visibility STEM Africa, which "promotes the stories of Africans — on the Continent and beyond — to inspire the next generation of leaders in STEM."
Heather Wolfe, MD, a hematologist and third-year Hematology and Oncology fellow conducting population-science research in the Oeffinger Lab (led by Kevin Oeffinger, MD), had the top abstract in the DCI Cancer Prevention and Control Research Program. The title of her abstract — “Prevalence, screening, treatment, and complications of osteoporosis and osteopenia in Medicare patients with chronic lymphocytic leukemia (CLL)” — is named for a retrospective cohort study she’s leading as part of DCI’s Onco-Primary Care initiative.
CLL is the most common type of leukemia seen and treated in adults with approximately 20,000 new cases diagnosed each year in U.S. The average age at the time of diagnosis is 72. With dramatic improvements in treatment, Wolfe explained, patients are now living decades following their diagnosis to the point where CLL progression plays a role in cause of death in only 35% of patients. In more than 20% of CLL patients, the cause of death is completely unrelated to CLL.
“Many of our CLL patients are older and we know that the aging process is associated with the development of other co-morbidities,” said Wolfe. “Some of these co-morbidities such as hypertension and atrial fibrillation have been studied in CLL, but other issues such as bone health have been left out. Bone health has been studied in other malignancies such as prostate cancer and breast cancer. And in these patients we have clear guidance on bone density screening as well as when and how to treat these patients, if it’s indicated. However, few studies have been published on bone loss in adult patients with hematologic malignancies.”
Having CLL and being treated for CLL, Wolfe explained, raises questions such as: “How does CLL affect bone density? How does treatment affect bone density? And how does CLL treatment promote frailty, decreased mobility, and potentially an increased risk of falls?”
“A fall with a fracture in one of these patients can lead to functional decline, potentially requiring us to hold or discontinue life-prolonging therapy," she argued. "In order for us to maintain both quality and quantity of life in these patients, we need to catch and treat this issue early on.”
Wolfe’s survivorship-issues research is currently supported by a T32 NIH training grant.
Michael P. Plebanek, PhD, a postdoctoral associate with the Hanks Lab, had the top abstract in the DCI Immuno-Oncology Research Program for his basic-science project — “Characterization of a Novel Tolerogenic Dendritic Cell Subset in the Tumor Microenvironment.”
Plebanek received his PhD from Northwestern University in Chicago where he published research showing that cancer exomes induce immune surveillance to the metastatic niche. Recruited to DCI by Brent Hanks, MD, PhD, the two are teaming up to ask how mono-nuclear cells in the metastatic niche might contribute to cancer perpetuation and spread. Answering this question would carry a high impact because most cancer deaths are due to metastases that result from an evasion of the immune system by the tumor.
Jiung (Peter) Nam had the winning abstract in the DCI Precision Cancer Medicine and Investigational Therapeutics Research Program: "Two-Sided Therapy: STK3 a potential dual Breast Cancer and Cardio-Protective Target.”
A third-year undergraduate (Trinity College of Arts and Sciences and Department of Pathology, Duke University School of Medicine) who’s studying biology and computer science, Nam joined the Macias Lab as a research assistant in September 2020 with the goal of learning more about precision medicine, research and molecular biology lab techniques.
He’s currently completing an independent translational-research study under the mentorship of lab director and assistant professor in the Department of Pathology Everardo Macias, PhD, and Pathology graduate student Amelia Schirmer investigating the cardio-protective effects of tumor suppressor pathway inhibition; specifically the STK3 pathway. Nam is interested in pursuing an MD/PhD following graduation.
Diana A. Odhiambo, BS, had the top abstract in the DCI Radiation Oncology and Imaging Research Program for her basic-science work “Evaluating the therapeutic potential of a small molecule ATR inhibitor combined with radiotherapy for head and neck squamous cell carcinoma.”
Odhiambo is working as a Research Technician II in the Mowery Lab, led by Yvonne Mowery, MD, PhD, which utilizes genetically engineered mouse models, patient-derived samples and molecular biology techniques to study head and neck cancer development and progression as well as the interplay between radiation therapy and the immune system in sarcoma and head and neck cancer.
Odhiambo, who’s from Kenya, received an African Education Fund grant to support her undergraduate studies at Benedict College in Columbia, South Carolina, where she majored in Biology and graduated summa cum laude in 2020. Since joining the Mowery Lab in 2020, she’s been the lead researcher on pre-clinical studies of the small molecule ATR inhibitor and recently presented her data with an oral presentation at the Radiation Research Society Meeting. She's an aspiring physician scientist and is currently applying to MD/PhD programs with a goal of leading her own lab focusing on immune oncology and cancer biomarker discovery.
Head and neck squamous cell carcinoma is the sixth most common cancer worldwide with risk factors including tobacco, alcohol consumption and high-risk HPV infection. Current treatment modalities include surgery, radiation therapy and chemotherapy.
“Even in the face of this aggressive, multimodal treatment of disease, outcomes still remain poor for patients presenting with locally advanced HPV negative disease… Unfortunately, also, in the past decade, there really hasn't been any advancement in the treatment of head and neck squamous cell carcinoma. And additionally, there are limited treatment options for recurrent and metastatic disease,” said Odhiambo. “This calls for new therapeutic approaches that can enhance radiation response and improve patient outcomes."
Austin Eckhoff, MD, had the top DCI Cancer Risk, Detection and Interception Research Program abstract: “Multidimensional Immunophenotyping of Intraductal Papillary Mucinous Neoplasms Reveals Novel T cell and Macrophage Signature.”
As a fourth-year General Surgery resident working in the Allen Lab under the mentorship of Peter Allen, MD, she’s currently conducting translational research into the role of inflammation and immunology in the progression of intraductal papillary mucinous neoplasms (IPMNs) to pancreas cancer. IPMNs are cystic lesions of the pancreatic ductal epithelium that have the potential to progress to pancreatic cancer.
“Little is known about what is driving these lesions to cancer progression … Understanding the mechanism of this progression provides a valuable opportunity to intervene prior to the onset of cancer,” she explained before detailing her discoveries related to the mechanism (s) behind IPMN progression.
Selena J. Lorrey, BA, a fourth year PhD Candidate in the Duke Brain Tumor Immunotherapy Program, presented her basic-science dissertation research, which was conducted in the Fecci Lab (led by Peter Fecci MD, PhD): “Arrestin’ Peripheral Immune Deficits in Glioblastoma: A role for beta-arrestin 2 and adrenergic signaling.” Hers was the winning abstract in the DCI Neuro-Oncology Research Program.
Lorrey's current research focuses on systemic immune dysfunction in the setting of adult glioblastoma, an aggressive brain cancer that kills 95% of patients within the five years following diagnosis despite available treatments that include surgery to remove the tumor, chemotherapy and radiation. Lorrey with Jessica Waibl Polania (also a fourth-year PhD candidate working in the Fecci Lab) are the recipients of the 2021-2022 Paul and Lauren Ghaffari Graduate Fellowship. The two are working together “to discover ways to successfully target and treat aggressive brain cancers with the power of the immune system.” (LEARN MORE: Searching for A Higher Gear in the Fight Against Brain Cancer)
With a particular research interest in the interactions between the nervous and immune systems in the context of cancer initiation and progression, Lorrey plans to pursue a career in basic research and translational medicine in the setting of immune-oncology.
In addition to presentations by the seven DCI trainees, two DCI investigators took center stage: Chuan-Yuan Li, DSc, vice chair for Research in the Dept. of Dermatology, professor in the departments of Dermatology and Pharmacology and Cancer Biology, and Tomi Akinyemiju, PhD, associate director for Community Outreach, Engagement and Equity (COEE) at DCI; director for Inclusion and Diversity in the Department of Population Health Sciences; associate professor in the Department of Population Health Sciences; associate research professor, Duke Global Health Institute; and an instructor in the Department of Obstetrics and Gynecology.
The Li Lab focuses on the molecular mechanisms of tumor response to cytotoxic cancer therapy and immunotherapy.
"His lab recently discovered several critical pathways regulating tumor response to immune checkpoint inhibitor therapy — discoveries with translational potential," said deputy director of DCI, Steven Patierno, PhD, introducing his colleague and lab-hallway mate, Li.
Most recently, Patierno described, Li's group was responsible for identifying many of the unconventional roles of apoptotic caspases beyond acting as “executioners” of unwanted or damaged cells or tissues and the unexpected roles of DNA double-strand break (DSB) repair factors (beyond just repairing damaged DNA). In fact, he found that apoptotic caspases and DNA DSB repair factors had a role to play in resistance to cytotoxic cancer treatment and played non-canonical roles in “disparate biological and pathological processes such as radiation-induced genetic instability and carcinogenesis, wound healing and tissue regeneration, induced pluripotent stem cell induction, spontaneous and stochastic generation of cancer stem cells, and cancer immunotherapy.” (LEARN MORE: Int J Radiat Biol 2021 Jul 14;1-10)
Li's special presentation at the DCII Scientific Retreat covered two immunotherapy-related projects his lab's been working on:
- the role of PCSK9 — a protein that regulates the amount of cholesterol in the bloodstream and that’s found in high amounts in LKB1/STK11- mutated advanced non-small cell lung cancer tumors — in driving immune evasion in this type of advanced NSCLC. Li specifically addressed how PCSK9 might play a key role in these patients' known resistance to immune checkpoint inhibitor drugs and the possibilities for using the cholesterol-control PCSK9-inhibitor drugs evolocumab (Repatha) or alirocumab (Praluent) to overcome this immunotherapy resistance in LKB1/STK11- mutated NSCLC. (LEARN MORE: Li Awarded Grant for Cholesterol-Control-Drug-Repurposing Research)
- unpublished work in his lab related to the VHL gene, a protein that helps control cell growth, cell division, and other important cell functions, and in mutated form can cause kidney cancer and tumors of the brain, spinal cord, eye, ear, adrenal glands, pancreas, or other parts of the body.
Akinyemiju, for her part, focused on the current work, challenges faced, and future goals of COEE in her multi-pronged presentation — “Catalyzing Community-Engaged Research to Reduce the Burden of Cancer in the DCI Catchment Area.”
“We have three high level goals that we're trying to accomplish,” she began. “One is to engage meaningfully, respectfully and collaboratively with our community partners. Second is to strengthen partnerships between our communities and scientists here at DCI to advance novel discoveries that will benefit our community members. And third is to disseminate and implement evidence-based strategies and policies to reduce the burden of cancer in our catchment area.”
Akinyemiju, a social and molecular cancer epidemiologist with expertise in epidemiologic methods, translational research, health disparities and global health, acknowledged that there’s “a lot of work to do” in reducing the burden of cancer and “big challenges in our communities that we’re charged with addressing.”
She noted the geographic diversity of DCI’s catchment area that covers part of Southern Virginia, most of central North Carolina and northern South Carolina and includes rural, urban and suburban counties, and she described inequities in income, education, food security, and healthcare access across the region.
“About a quarter of our population has an annual household income that is less than $25,000 and about 16% of our population have less than a 12th grade education… It’s really important that our research and our science is relevant for those populations as well,” she said.
She also zeroed in on the cancer burden in North Carolina, specifically.
“About 20,000 Carolinians die of cancer every year,” she said. “We have a long way to go in terms of our ranking with related risk factors like smoking, exercise, obesity, high cholesterol, and high blood pressure.” (LEARN MORE: Dissecting Disparities in Cancer Outcomes)
Right on Key
Alan Ashworth, PhD, FRS, who hails from the UK, currently serves as president of the UCSF Helen Diller Family Comprehensive Cancer Center and senior vice president for Cancer Services at UCSF Health, delivered the keynote *O. Michael Colvin Memorial Lecture.
Before introducing Ashworth, Kastan reminded participants that Michael Colvin, MD, a former director of the Duke University Comprehensive Cancer Center, was “best known for working out the mechanism of many chemotherapeutic drugs, particularly cyclophosphamide, which is one of the first effective and one of the most commonly-used anti-cancer agents… and he made a significant contribution to the development of current stem cell therapies.”
Kastan also brought attention to Colvin’s strong advocacy for and development of cancer patient support services, his “fantastic mentorship” of trainees and other faculty members, and his “thoughtful and calm” leadership approach.
“His wife Macy remains an active member of the DCI Board of Advisors and is on the call today,” Kastan noted, before addressing Macy Colvin directly over Zoom. “Unfortunately, we're not in person otherwise we would be giving you a bouquet of flowers as usual.”
Introducing Ashworth, Kastan said, “Alan probably needs no introduction because the work that he's done has had such a profound impact on our field.”
Kastan went on to introduce Ashworth as a key member of the team that discovered the BRCA2 gene in 1995, which is linked to an increased risk of breast, ovarian and other cancers. In 2005, Ashworth’s lab identified a way to exploit genetic weaknesses (using synthetic lethality) in cancer cells with mutated BRCA1 or 2 genes, leading to a new approach to cancer treatment, PARP inhibition. At least four different PARP inhibitors have now been approved by the FDA for the treatment of ovarian, breast, pancreatic and prostate cancer based on his work. This work was named by Nature as one of the top 20 discoveries in cancer in the 21st century and Ashworth continues to develop new treatments for cancer using genetic principles.
In his keynote — “Synthetic Lethal and Genetic Approaches to Cancer Therapy” — Ashworth talked participants through the development of PARP inhibitors (“I'm going to talk about DNA-repair defects as Achilles heels for BRCA- associated cancers and how we parlayed this deficit into a therapeutic approach”), more recent PARP research, and thoughts on where the field is, then concluded with a presentation of unpublished data around ADP-ribosylation and viral infection.
*Before his loss in 2013, O. Michael Colvin, MD, served as Director Emeritus of the Duke University Comprehensive Cancer Center and Professor Emeritus of Medicine at Duke University School of Medicine. As co-leader of the Duke Cancer Center’s Experimental Research Program, his many achievements included pioneering work on drugs that damage the genetic material causing cancer cells to replicate. Begun in 2015, the O. Michael Colvin Memorial Lecture has been a featured highlight at every DCI Scientific Retreat since.
CIRCLE PHOTO (TOP): Emmanuela Bonglack, a 5th year PhD candidate in the Department of Pharmacology & Cancer Biology, who received the 2021 Robert and Barbara Bell Basic Science Cancer Research Award for her basic-science abstract: "Targeting viral lymphomas through lactate export-associated metabolic vulnerabilities.”