Making Pigs Fly? Investigators Up To The Challenge
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 27th 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, 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
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.)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
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.
Circle photo (top): Deputy Director of the National Cancer Institute, Douglas R. Lowy, MD, asks critical questions