Making Pigs Fly? Investigators Up to the Challenge at Scientific Retreat

When Duke Cancer Institute researcher Christopher Pirozzi, PhD, was an intern doing stem cell research in Australia, he spotted a child’s mobile of a pig with wings in one of the director’s offices. He said it embodied exactly what research meant to him — making the seemingly impossible, possible.

“People think there aren’t cures for some diseases, but I disagree,” said Pirozzi, who was honored at DCI’s 5th Annual Scientific Retreat for his ground-breaking work on malignant brain tumors with this year’s recipient of the Robert and Barbara Bell Award for Basic Science Cancer Research. “It isn’t all doom and gloom.”

If the research presented at the annual gathering — held on October 27 at Bay 7 in the American Tobacco District of Durham — is any indication, “making pigs fly,” in cancer terms, maybe isn’t so far off.

“I’m so proud of the extraordinary work that’s done by investigators and trainees here at the Duke Cancer Institute,” said DCI executive director Michael Kastan, MD, PhD introducing the eight winners of DCI’s abstract competition, including Pirozzi, across the categories of basic science, population science, translational and clinical research. 

The up-and-comers selected this year are working in the fields of neuro-oncology, hematologic malignancies and cellular therapy, cancer control and population science, and radiation oncology. They had the opportunity to present their work in front of about 230 Duke physicians, researchers, and staff, plus deputy director of the National Cancer Institute, Douglas R. Lowy, MD, this year’s guest speaker. 

Pirozzi, a postdoctoral fellow in the DCI Neuro-Oncology research program who works in the onco-genomics Yan Lab, was first up. In addition to the Bell award, he received a presentation award in the field of basic science research for his abstract — Mutant IDH1 Disrupts the Mouse Subventricular Zone and Alters Brain Tumor Progression — the findings of which were also published in the journal of Molecular Cancer Research this year.  

“We call that a hat trick,” said retreat emcee Christopher Counter, PhD, introducing Pirozzi.

Pirozzi’s research builds on a discovery nearly a decade ago led by Hai Yan, MD, PhD, of genetic mutations in the IDH1 and IDH2 genes of malignant gliomas, the most common type of brain tumors and among the most frequent causes of cancer death in children and young adults. 

“This was rather significant because this mutation, in IDH1, was expressed in more than 80 percent of low-grade gliomas, and gave us a foundation to start targeting them therapeutically,” explained Pirozzi. “What we’re doing now is establishing models that can be used to understand the progression of the disease. We’re trying to figure out how to harness the power of the immune system to target these mutations, to ultimately cure the disease.”

Precision Oncology, Reaching Targets

A precision medicine approach was also central to the second winning abstract for basic science research — High Mobility Group Box 1(HMGB1) Regulates Self-renewal of Hematopoietic Cells in Myelodysplastic Syndromes — by Yuet Fong Kam, PhD, a postdoctoral fellow in the Phuong Doan Lab and the DCI Hematologic Malignancies & Cellular Therapy research program. Kam elaborated on the role of the HMGB1 protein in myelodysplastic syndromes (MDS), a group of diverse bone marrow disorders characterized by ineffective hematopoiesis — a condition in which the bone marrow does not produce enough healthy blood cells. (MDS kills about half of its high-risk patients within a year of diagnosis, even following standard chemotherapy.)

Kam and her team discovered that HMGB1 was highly expressed in MDS-L and postulated that HMGB1 could be a biomarker of MDS. Her research group hypothesized that modulation of the innate immune system in MDS could facilitate normal production of blood cells. She hopes that the result of their ongoing studies “will demonstrate that pharmacologic inhibition of HMGB1 is an unexploited pathway for the treatment of MDS, and possibly for other hematologic diseases.”

Targeted therapy was also a theme of the retreat’s faculty presentation — Mining the Complexities of Estrogen Receptor Signaling Pathways in Breast Cancer for New Therapeutic Targets — by Donald McDonnell, PhD. McDonnell, chair of the Department of Pharmacology & Cancer Biology at Duke and co-director of the DCI Women’s Cancer research program at Duke Cancer Institute. He addressed his lab’s progress in breast cancer research and the future of breast cancer therapy.

“Our group has been at the forefront of developing new classes of estrogen receptor modulators for the treatment of estrogen receptor positive breast cancer, the most common type of breast cancer,” he said. “Tamoxifen and aromatase inhibitors have completely changed the landscape of therapy in this disease. Better science has enabled better drugs and now there are several drugs in the clinic that either directly or indirectly come from research funded by the Duke Cancer Institute, done in our department.”

McDonnell’s lab has also recently identified some new targets and molecules that will interfere with those targets to block cancer growth, and has near-term plans to bring those to clinical trial. His group is also developing strategies they think will allow immunotherapy to be used in breast cancer.

“It’s my hope that we can move from saying we are very good at treating cancer to really use the word cure,” said McDonnell.

Doing More With Less

The NCI’s Lowy, invited to the retreat to deliver the third annual *O. Michael Colvin Memorial Lecture, kicked off his talk — HPV-Associated Cancers: Doing More With Less — with his own definition of precision medicine that “includes prevention and screening at least as much as it includes treatment.”

Best known as one of the scientists credited with enabling the development of human papillomavirus (HPV) vaccines for the prevention of cervical cancer, and a listed inventor of the vaccines by Merck and GlaxoSmithKline, Lowy’s talk zeroed in on “the problem of cervical cancer” and what can be done to eradicate it as a public health problem worldwide. (In the developing world, he said, there’s projected to be a 50 percent increase in the number of deaths from cervical cancer over the next 15 years)

“If you like targeted interventions for the treatment of cancer, you will love them for the prevention and screening of cancer,” said Lowy, who also touched on the potential future use of HPV vaccines to protect against other HPV-positive cancers, including anal cancer, oropharyngeal cancer, vaginal cancers, vulvar cancer, and penile cancers. Lowy noted there’s been a three-fold increase in HPV-positive oropharyngeal cancer in the U.S. during a relatively recent 25-year period; a disease whose patients are 75 percent male.

“Basic research led to the identification of HPV as the cause of several cancers and to the development of HPV-based screening and the HPV vaccine,” said Lowy. “Second generation HPV screening and second generation HPV vaccines can achieve an even greater reduction in HPV-associated disease. I really do believe that the elimination of HPV-associated cancer as a worldwide public health problem may soon be feasible.”

*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. Colvin was a founding senior editor of Molecular Cancer Therapeutics. 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.

Translational & Transformational Research

Barriers to understanding how cancer works are also being lifted at the Dorothy Sipkins Lab, where Gaia Cantelli, PhD, a postdoctoral fellow in the DCI Hematologic Malignancies & Cellular Therapy research program, is figuring out how acute lymphoblastic leukemia (ALL) cells, which can’t breach the blood brain barrier, enter the central nervous system. Central nervous system metastasis is characteristic of all subtypes of ALL. 

“What we’ve uncovered with our current research is a new model (pathway) for these cells to enter the central nervous system (CNS) and cause paralysis and other CNS symptoms,” said Cantelli, who was awarded by DCI in the translational research category for her abstract Acute Lymphoblastic Leukemia Cells Hijack a Neuronal Pathfinding Mechanism to Invade the Central Nervous System. “This is an absolutely huge problem in the clinic both in terms of pediatric patients and adult patients that has a huge impact on patient survival and quality of life.”

In the mechanism that Cantelli described, the acute lymphoblastic leukemia (ALL) cells migrate into the central nervous system along vessels that passage directly between vertebral or calvarial bone marrow and the subarachnoid space.

“Future studies may reveal that this unique ALL trafficking pathway is involved in normal immune surveillance or inflammatory processes,” she wrote in her abstract. “Exploring the interactions between normal and malignant immune cells and these vascular scaffolds may thus reveal multiple points of intervention to treat CNS invasive processes.”

Wei Huang, MD, PhD, a second-year postdoctoral fellow in the Nelson Chao Lab in the DCI Hematologic Malignancies & Cellular Therapy research program, also received a translational research award. In her abstract — Fecal Microbiota Transplant to Restore the Recipient Microbiota Effectively Attenuates Graft-Versus-Host Disease in Mice — she explained the important role that gut microbiota play in intestinal homeostasis (stability) and outcomes after stem cell transplantation.

“Post-transplant loss of microbiota diversity in patients has been associated with increased infections, graft-versus-host disease, disease relapse and treatment-related mortality,” Huang wrote. “Case studies suggest that fecal microbiota transplant may helped restore the microbiota, suppress T-cell responses in graft-versus-host associated organs, and improve (ameliorate) graft-versus-host disease.”

Huang, who came to Duke after earning her MD in China, reflected: “When I was an intern in the hospital, I noticed that a lot of the patients who went through bone marrow transplantation, although it saved their lives, had complications and very poor quality of life. We want to find new solutions to this disease and improve the quality of life of these patients.”

Improving Patient Outcomes

Patient outcomes were also the focus of a research project by Daphna Spiegel, MD, MS, a trainee in the Joseph Salama Lab in the DCI Radiation Oncology and Imaging research program. She received a presentation award in the clinical research category for her work on Long-term Outcomes of Nonoperative Management for Locally Advanced Rectal Cancer in the Veterans Health Administration.

Her research team found that patients who underwent chemoradiation but didn’t undergo surgery and achieved a clinical complete response rate had similar overall survival and disease-specific survival compared to patients who underwent chemoradiation plus surgery and had a pathologic complete response.

Fumiko Chino, MD, won the other presentation award in the clinical research category, for her abstract Healthcare Disparities in Cancer Patients Receiving Radiation: Changes in Insurance Status after Medicaid Expansion under the (Affordable Care) Act.

Chino, a trainee in the Junzo Chino Lab in the DCI Radiation Oncology and Imaging research program, compared insurance status in cancer patients receiving radiation before and after Medicaid expansion under the Affordable Care Act.

“What we found is that the Affordable Care Act really did work to reduce un-insurance rates for patients and this means so much for cancer patients because we know that un-insurance leads to worse outcomes for cancer,” she said, adding that Medicaid expansion significantly decreased the un-insurance rates of cancer patients receiving radiation.

States that didn’t expand Medicaid, she noted, appeared to have healthcare disparities that were not found in expanded states.

The population science research awards were given to Julia Butt, PhD, a research scholar in the Meira Epplein Lab, and Andrea Sitlinger, MD, a hematology-oncology fellow in the Yousuf Zafar Lab — both part of the DCI Cancer Control & Population Sciences research program that aims to reduce the cancer burden in DCI’s catchment area.

In her project, Antibody Responses to Streptocuccus Gallolyticus Proteins in a Colorectal Cancer Cohort Consortium, Butt’s team was able to reproduce an association of antibody responses to the Streptococcus gallolyticus subspecies gallolyticus (SGG) pilus protein Gallo2178 with a risk of developing colorectal cancer.

“More detailed analysis will help to identify risk factors for antibody responses to SGG infection and to specify how long before diagnosis antibody responses to the infection might serve as a marker for colorectal cancer development,” explained Butt.

Andrea Sitlinger, MD, presented on Insurance Design and Out-of-Pocket Costs: A Comparison of Oral and Intravenous Treatment for Chronic Lymphocytic Leukemia. A cancer patient’s out-of-pocket costs for intravenous versus oral chemotherapy can vary with their insurance plan. While 43 states have enacted laws to mandate cost-sharing parity between oral and IV chemotherapy out-of-pocket costs, Sitlinger revealed that, in the case of CLL patients taking the commonly prescribed CLL treatments bendamustine/rituximab (IV) or ibrutinib (oral), there was little evidence these laws actually lowered their costs.

“In the Affordable Care Act, the maximum out of pocket cost was over $7,000 in 2017,” she said. “We found that patients receiving either bendamustine/rituximab (IV treatment) or ibrutinib (oral) reached their maximum annual out-of-pocket caps in approximately one month.”

Her research team found that drug costs (more than professional fees, lab and imaging fees) contributed most to patients reaching these caps.

“Over the years there’s been a shift in insurance to move more and more costs to patients,” said Sitlinger, pointing out the possible consequences of this financial toxicity, including bankruptcy and non-adherence to their medications. “Other methods need to be explored for reducing patients’ financial burden from these novel yet expensive therapies.”

With no shortage of ideas, the retreat wrapped up with a poster session — 81 in all — sparking discussion into the night about the latest advancements in cancer science, treatments, and care and what comes next.