What can green lizards and “dark matter” teach us about cancer?
First a bit about genomic dark matter: It refers to DNA sequences that make up a large part of the human genome but do not encode proteins, some of which are known as IncRNAs. They play a role in tissue development, tumor formation, and cancer progression—but many key questions remain about dark matter and IncRNAs.
University of Rochester Medical Center scientist Bin Zhang, Ph.D., and a team of researchers discovered how IncRNAs function and evolve in the genomes of green lizards. Their work is published in Cell Reports, in collaboration with scientists at Cold Spring Harbor Laboratory, Long Island, N.Y., where Zhang worked before joining URMC in 2015.
One particular IncRNA—MALAT1 (Metastasis-Associated Lung Adenocarcinoma Transcript 1)—was first associated with lung cancers that were likely to spread and later found to be over-abundant in many other tumor types. The MALAT1 gene contains a unique tail structure that stabilizes the RNA molecule. Zhang’s team pioneered a series of computer models and algorithms allowing them to turn the tail structure into a searchable module. They discovered a class of 130 different vertebrate IncRNAs with similar structures to MALAT1, and then further conducted evolutionary studies into the activity of the IncRNAs in green lizards. The National Cancer Institute and National Institute of General Medical Sciences funded the study.
An assistant professor in Pathology and Laboratory Medicine and Pediatrics, Zhang also specializes in clinical cytogenetics and molecular genetics. He conducts detailed genetic tests and evaluates blood, bone marrow, lymph nodes, and other tissues for cancer.
Leukemia is one of the hardest cancers to treat, but scientists have discovered a new, targetable pathway in one of the worst subtypes of the disease.
The study, although only relevant in mice and human cell cultures at this point, is important because researchers found that an existing drug, known as creatine kinases inhibitor, is effective at attacking acute myeloid leukemia (AML) in the laboratory.
University of Rochester Medical Center and Wilmot Cancer Institute scientists Archibald Perkins, M.D., Ph.D., and Yi “Stanley” Zhang, Ph.D., teamed up with researchers at Harvard University and the Massachusetts Institute of Technology to study a particular gene, EVI1. When this gene is active, certain types of leukemia and some solid tumors, such as ovarian cancer and some breast cancers, are virtually untreatable.
Their study recently was published in the high-impact journal Nature Medicine. The group showed that when EVI1 is abundant in leukemia, it changes the metabolism of immature blood cells as they progress toward becoming cancer—but also leaves EVI1-positive cancers vulnerable to treatments that can strike down that pathway.
The Perkins/Zhang laboratory in the Department of Pathology and Laboratory Medicine has been investigating the EVI1 gene for several years, resulting in a solid track record of publications on the topic. Their goal is to discover new treatments that will target the underlying pathways involved in EVI1-positive cancers. The Perkins/Zhang data supported Harvard’s and MIT’s investigation of what drives the EVI1 gene.
Leukemia is a type of blood cancer in which abnormal blood cells crowd out the healthy white blood cells responsible for fighting infection. More than 10 different major subgroups of leukemia exist. Many types of leukemia are resistant to treatment, although some patients with AML and other blood cancers can achieve long-term remission if they qualify for a stem cell transplant. Wilmot’s Blood and Marrow Transplant Program is the only program in the Finger Lakes region to offer that therapy.
The Nature study was recently highlighted by the American Association of Cancer Research. Perkins and Zhang are working on other leukemia studies as well, supported in part by Wilmot seed funds and by the URMC Clinical & Translational Science Institute.
This month, Chawnshang Chang, Ph.D. received a U.S. patent for a new way to treat and prevent the recurrence of prostate cancer.
In his description Chang notes that patients who are treated with the commonly used method of androgen deprivation therapy (ADT) often experience a return of the disease, even after remission.
This second wave of prostate cancer has no known cure and there are few treatment options available. According to the patent, Chang’s method can reduce the chance of recurrence of prostate cancer in patients who have been treated with ADT. To do this, patients are given an anti-androgen agent that prevents cancer cells from rapidly multiplying.
Chang lists several anti-androgen agents that can be used in this way to suppress cancer growth, one of which is ASC-J9, a chemically modified derivative of ginger. One of the most significant findings in this patent is that the cancer-fighting chemotherapy drug cisplatin is able to re-sensitize cancer that is resistant to the anti-androgen drug, enzuluamide.
This is the third patent for Chang, who is the George Hoyt Whipple Distinguished Professor of Pathology, Urology, and Radiation Oncology at URMC and Wilmot Cancer Institute.
Some pathologists find themselves torn between research and clinical practice, but Dr. Jiaoti Huang, MD, PhD isn't one of them.
“If things work well, you don’t have to spend a lot of effort balancing the work,” he said. “For me, the more clinical work I do the more problems and issues that I discover for my research.”
Huang joined the URMC Pathology faculty as an assistant professor in 2000 and was promoted to full professor in 2007. He left in 2008 to work at UCLA until making the move to Duke University, where he was named Pathology Department chair in January 2016.
Since then, he has continued to thrive, receiving, the Synergistic Idea Award from the Department of Defense Prostate Cancer Research Program in February.
His successful career has led Dr. Huang to become an authority on prostate cancer research. His most recent breakthrough began when he observed that advanced-stage patients diagnosed with adenocarcinoma were inexplicably seeing their cancer transform to small cell carcinoma – an incurable and rapidly progressing form.
Supported by two active grants including a Stand Up to Cancer Dream Team Award, he worked with a team that performed 250 biopsies of metastatic prostate cancer that has been heavily treated with conventional and newer drugs.
From there, he discovered novel histologic features of metastatic prostate cancer and the molecular mechanism responsible for the transformation from a relatively indolent to a very aggressive form. Knowing more about the molecular basis of this phenomenon can now help physicians develop better treatment plans for their patients.
The results of the project were used to apply for a new R01 grant from the National Cancer Institute which started July 1. None of this would have been possible without working in a clinical setting, Huang says.
“This project was born from my clinical practice," he said. "If that is the basis of your research, your clinical activity does not really interfere."
He has received teaching awards at both URMC and UCLA and has seven grants that are currently active, including three from the National Cancer Institute. Huang attributes much of his success to the support and encouragement he received early on from former colleagues in Rochester (notably, Drs. Daniel Ryan and Brendan Boyce).
“The Pathology Department at the University of Rochester creates a conducive environment for junior faculty to go on with their academic careers,” he said.
Now Dr. Huang is looking to bring that same culture to his a much larger institution, understanding the need to support young, incoming faculty rather than “throwing them into the swimming pool” and expecting them to survive.
Outside of work, he enjoys exercise, cuisine, and travel. He's gone to several Duke basketball games and has even met the legendary Coach K. He describes the experience of seeing the team's championship trophies, photos and memorabilia as “mesmerizing.”
He and his wife, Hong, have two children – Kevin, who is a freshman studying mathematics at Duke, and Katherine, a Harvard graduate who works in finance in New York City.
UR Medicine Central Labs and UR Medicine Labs have been providing essential, behind-the-scenes services for sites across the U.S. participating in a clinical trial for cancer immunotherapy.
An Elmira man was featured in the local news because he was the first person enrolled at the Wilmot Cancer Institute to participate in the national clinical study of CAR T-cell therapy, which uses a patient’s own immune system to fight cancer. The trial is limited to people with certain types of lymphoma who have not responded to conventional treatment, and who meet strict eligibility criteria.
UR Medicine labs first partnered with a pharmaceutical company in 2015 to adapt and validate as assay for the presence and quantity of CAR19 T-cells in a patient’s blood, based on an a model developed by the National Cancer Institute. Since then the UR labs team has worked to refine and validate the assay for large-scale implementation.
The immunotherapy trial is designed to manipulate the body’s built-in defense mechanisms to fight cancer. Regular antibodies can be effective in fighting infection but are not so useful in killing tumor cells. Research has shown that a certain type of lymphocytes (a disease-fighting category of white blood cells) called T lymphocytes can target and kill lymphoma cells.
These "T-cells" must first receive permission from the body to fight, however. The patient's T-cells are introduced to DNA that first incorporates itself into their genome to produce a new protein – a chimeric antigen receptor (CAR) – that activates each cell, giving it the ability to detect and bind to a lymphoma cell.
"You're bypassing a lot of the regulatory checks and balances that have prevented previous attempts to generate tumor-killing T-cells," said Dr. Dan Ryan, director of Central Labs. "If (the cells) don't become activated, they die off."
Bill Crowe and Paul Rothberg from the Molecular Diagnostics Laboratory are leaders of the group that expanded the NCI test. Central Labs closely monitors test results from participating patient treatment sites across the U.S., and a vast network of lab professionals completes a series of time-sensitive steps.
Staff at Ridgeland Road assembles and sends out testing kits to each treatment site. The blood samples are then received via mail by Specimen Logistics staff six days a week. Technologists at the Tissue Typing Lab at Strong Memorial Hospital, Lymphoma/Leukemia Tissue Bank (SMH), Hematology Lab and Microarray Lab (Ridgeland) are responsible for processing and freezing all of the peripheral blood mononuclear cell blood tubes (PBMCs) for storage.
Phil Rock is a lab technician at SMH whose duties include tracking frozen samples for the CAR T-cell trial. He says the number of samples has skyrocketed since the trial began, which is a positive sign for immunotherapy.
"I think this trial, and the fact that (Central Labs) is growing is great for the department," said Rock. "I enjoy it immensely because having a hand in it allows me to use things that I went to school for and I've been trained to do that previously had no application."
Top: Clinical tech specialist, Jonathan Hoffmann, treats PBMC samples in the Human Leukocyte Antigen (HLA) Laboratory at URMC. Middle: Dr. Dan Ryan, director of UR Medicine Central Labs, which coordinates participation in clinical trials. Bottom: UR Medicine Central Labs kit production coordinator Deidra Davis, left, and Morgan Devaney.
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