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Inside research
Advancing cancer treatment
Translational research yields clinical trials for non-Hodgkin’s lymphoma
In the laboratory of Steven Grant, M.D., a researcher internationally recognized for his work in hematologic cancers including leukemias, lymphomas and multiple myeloma, exploring new paths of research and treatment in non-Hodgkin’s lymphoma is a top priority.
Each year in the U.S., nearly 75,000 new cases of various forms of lymphoma are diagnosed, resulting in nearly 20,000 deaths. Lymphoma represents a group of cancers that originate in the lymphatic system, which helps the body fight infection and disease. Understanding the causes of and treatments for lymphomas is of particular interest to the National Cancer Institute because their incidence has grown by nearly 80 percent in the last 30 years.
Grant, who is associate director for translational research at Massey, together with colleagues from VCU and two other leading cancer centers — the University of Rochester Medical Center’s James P. Wilmot Cancer Center and the Arizona Cancer Center at the University of Arizona — recently received a prestigious $11.5 million grant from the NCI to advance research and treatment in non-Hodgkin’s lymphoma.
Within the larger Specialized Programs of Research Excellence (SPORE) grant, which is led by James P. Wilmot Cancer Center investigators, the NCI awarded a five-year component SPORE grant to Grant.
Grant is the principal investigator of a project designed to improve the effectiveness of the proteasome inhibitor bortezomib, known as Velcade — an established lymphoma drug — with other targeted therapies. The goal is to improve its effectiveness in patients with diffuse lymphocytic B-cell lymphoma (DLBCL). Previous studies have shown that certain types of lymphoma, such as mantle cell lymphoma, often regress in patients treated with bortezomib, but that other forms of lymphoma, such as DLBCL, tend to be resistant to this agent.
Grant and his colleagues will work with Jonathan Friedberg, M.D., director of hematological malignancies clinical research at the Wilmot Cancer Center, on these studies. Each of the three collaborating centers anticipates participating in future clinical trials emanating from this project.
“It further validates our focus on translational research — the important area of bringing discoveries safely from laboratories to patients in the form of clinical trials,” said Gordon D. Ginder, M.D., director of Massey. “By collaborating with other cancer centers around the country, we have the opportunity to speed the development of better treatments for cancer.”
Within the SPORE, researchers at these institutions will participate in three other projects that will:
- Focus on manipulating mitochondrial function to enhance lymphoma cell death.
- Verify the existence of lymphoma stem cells — the initiating cells responsible for the initiation and maintenance of lymphomas. Identification of such lymphoma stem cells could give rise to new therapies specifically directed against those cells.
- Target aurora kinase, a cell cycle regulatory protein critical to lymphoma growth. Investigators will partner with a pharmaceutical firm to study a new investigational agent that inhibits aurora kinase activity in preclinical and, ultimately, clinical studies in lymphoma.
Only four other cancer research centers have been awarded SPORE grants for lymphoma, including Johns Hopkins University, the University of Iowa, City of Hope and Baylor College of Medicine.
Grant will collaborate with Massey researchers including Paul Dent, Ph.D., Department of Biochemistry and Molecular Biology; and Yun Dai, Ph.D., Girija Dasmahapatra, Ph.D., and Mohamed Rahmani, Ph.D., all of the Department of Internal Medicine.
A Phase II clinical study
In other work, Grant is the principal investigator of a NCI-sponsored Phase II clinical study for certain subtypes of non-Hodgkin’s lymphoma that launched this fall.
The study is based on research from Massey, as well as other centers, suggesting that combining two novel, recently approved drugs that have shown effectiveness in certain blood cancers may be effective in patients with diffuse large B-cell lymphoma or mantle cell lymphoma. The study is intended for patients whose disease has progressed following treatment with other regimens.
The investigators hope to learn whether these types of lymphoma respond to treatment with the combination of vorinostat, marketed as Zolinza, and bortezomib. They also intend to learn about the side effects of this drug regimen and whether certain features of these lymphomas might predict for response to this regimen.
Grant is among a number of researchers worldwide who have reported synergistic interactions between proteasome inhibitors such as bortezomib and histone deacetylase inhibitors such as vorinostat in leukemia and other hematologic malignancies. Other cancer centers are currently exploring this drug combination in patients with refractory multiple myeloma.
“Phase I data from studies in patients with multiple myeloma have given us a good idea of safe and appropriate doses of these two agents when they are administered in combination,” Grant said. “Such information has allowed us to open this as a Phase II study in patients with lymphoma to determine how effective this novel drug combination is in this setting.”
“The hematologic cancer research community has considerable interest in combination regimens incorporating these two important classes of new agents,” he said.
Within the mantle cell lymphoma patient group, the study will assess whether patients who have previously received bortezomib respond differently from those who have never been treated with bortezomib. Bortezomib administered alone has recently been approved for the treatment of patients with relapsed or refractory mantle cell lymphoma and was previously approved for patients with progressive multiple myeloma. Vorinostat has been approved for use in patients with cutaneous T-cell lymphoma.
DLBCL is a type of non-Hodgkin’s lymphoma that is usually fast-growing. It is the most common type of non-Hodgkin’s lymphoma and is characterized by rapidly growing tumors in the lymph nodes, spleen, liver, bone marrow or other organs. Other symptoms include fever, night sweats and weight loss. There are several subtypes of DLBCL.
Mantle cell lymphoma is a fast-growing type of B-cell non-Hodgkin’s lymphoma that usually occurs in middle-aged or older adults. It is marked by small- to medium-size cancer cells that may be in the lymph nodes, spleen, bone marrow, blood and gastrointestinal system.
Other NCI centers participating in this novel lymphoma study through the NCI’s Southeast Phase II Consortium include H. Lee Moffitt Cancer Center and Research Institute in Tampa, Fla., which is the coordinating center; UNC Lineberger Comprehensive Cancer Center in Chapel Hill, N.C.; Vanderbilt-Ingram Cancer Center in Nashville, Tenn. Also planning to participate are Montefiore-Einstein Cancer Center in New York; and New York Presbyterian Hospital/Weill Cornell Medical College, both of which are in the NCI-sponsored New York Phase II Consortium.
Fine-tuning precision: radiation oncology’s quest for a holy grail
An estimated 60 percent of cancer patients receive radiation therapy as part of their treatment. Many patients are benefiting from research and technologies that enable radiation to be delivered in less time with more effectiveness and precision than ever before.
At Virginia Commonwealth University Massey Cancer Center, radiation oncology researchers are spearheading a $10.7 million National Cancer Institute Program Project Grant to develop even better ways to target tumors through radiation while avoiding “collateral damage” to healthy tissue.
“Anyone can acquire treatment technology, but knowing how to maximize its potential by layering on advances in imaging science, biostatistics and biology is what will really improve cancer outcomes in patients,” said Jeffrey Williamson, Ph.D., chair of the medical physics division and principal investigator on the grant.
Image-Guided Adaptive Radiotherapy
Williamson and colleagues are parlaying their expertise into Image-Guided Adaptive Radiotherapy (IGART), which combines treatment planning imaging with treatment delivery systems to take radiation oncology into a new realm of precision.
“Human anatomy is dynamic and constantly changing, and organs shift and deform differently during each daily treatment,” Williamson explained. “We know that tumor shape and location in the patient’s body vary not only day-to-day, but in some cases second-by-second. By acquiring data on these motions and developing ‘four-dimensional’ models and predictions, we will be better able to predict where a tumor will be a second from now, rather than where it was a second ago, as we deliver radiation.”
In a treatment scenario, IGART’s imaging of the tumor will enable the radiation beam to adapt to even the most subtle changes of the tumor. A patient’s breathing, slight movements and bodily functions can cause such movements. By anticipating and adapting to these movements during the course of treatment, the outcome can be improved.
The project will enhance the safety and effectiveness of current treatments by incorporating quantitative and predictive image analysis into treatment planning. A key goal is to optimize on-board imaging, which is the main input data for IGART.
Conventional plans typically use 8- to 20-millimeter margins that allow normal tissue damage. “We might be able to reduce that margin by as much as 80 percent, or 6 to 16 millimeters, by combining adaptive planning and 4-D modeling,” Williamson said.
One of the technologies being adopted for the project functions much like a GPS and will be implanted in tumors to provide real-time feedback to scientists. The information on tumor movement will be updated 10 times per second.
Clinical studies
Researchers will accrue patients with lung, cervical or prostate cancer to participate in the IGART project. They expect to enroll about 25 patients from each cancer type for the first two years of study.
Using state-of-the-art technologies that provide images to guide the delivery of radiation doses, researchers first will carefully examine the movement of tumors and then employ adaptation techniques based on the unique characteristics of those tumors.
“By updating the 4-D anatomy as patients are treated, we can adapt or modify the treatment daily or, if necessary, on a second-to-second basis to accommodate anatomical and biological changes,” Williamson said.
NCI Program Project Grants: Few and far between
About a dozen leading institutions in the U.S. hold NCI Program Project Grants for radiation oncology. Of these, only Massey and Massachusetts General Hospital have grants in both biology and physics within their radiation oncology programs. These grants tend to lead to proof-of-concepts and new standards of treatment for cancer treatment nationwide.
The other radiation oncology NCI Program Project Grant at Massey is titled “Genetic Modulation of Cellular Radiation Response,” which is now in its eighth year under the leadership of Kristoffer Valerie, Ph.D.
The IGART project will involve the contributions of dozens of researchers at VCU. In addition to Williamson, principal investigators include radiation oncology faculty members Jeffrey Siebers, Ph.D.; Martin Murphy, Ph.D.; Nesrin Dogan, Ph.D.; and Paul Keall, Ph.D., an adjunct professor at VCU who is also director of radiation oncology physics at Stanford University.
New approach to treating breast cancer
For decades, the standard treatment approach for breast cancer patients requiring surgery has been to surgically excise the tumor and follow up with chemotherapy and then radiation.
In the mid-90s, Harry Bear, M.D., Ph.D., a surgical oncologist and director of the Breast Health Center at Massey, began exploring a new approach — neoadjuvant therapy — in which chemotherapy is given before the surgery rather than after.
Bear’s interest in neoadjuvant therapy has developed into his national leadership role with the National Surgical Adjuvant Breast and Bowel Project, which sponsors clinical studies that have the ultimate goal of determining which patients are the best candidates for this new order of treatment, as well as which chemotherapy they should have within that treatment plan.
“Giving chemotherapy before surgery in many cases will shrink the tumor, which may allow for lumpectomy rather than mastectomy and also may allow for a better surgery and disease control,” said Bear, who presented “Surgical Issues of Neoadjuvant Breast Cancer Treatment” at the 2008 Annual Breast Symposium of the American Society of Clinical Oncology. “We’re also exploring whether chemotherapy before surgery can reduce the need for lymph node dissection.”
The therapy generally is considered for patients with tumors larger than 2 centimeters, with lymph node involvement or those who have inflammatory breast cancer — a more dangerous form of cancer that presents more like a rash than a tumor.
Although two large clinical studies thus far have shown that survival rates are overall the same among patients with and without neoadjuvant therapy, the neoadjuvant approach can be beneficial.
“If we can make the tumors smaller before surgery, it can have an impact on how invasive the surgery is, which in turn affects the patient’s quality of life,” Bear said.
Tackling pancreatic cancer with chemoprevention gene therapy
In the U.S., approximately 37,000 new cases of pancreatic cancer are diagnosed each year. It’s one of the most lethal and treatment-resistant forms of cancer and has a five-year survival rate of less than 5 percent. Currently there is no effective chemotherapy or radiation therapy to fight it, but researchers at Massey are working to change that.
In the laboratory of Paul B. Fisher, M.Ph., Ph.D., professor and chair of the Department of Human Genetics in the VCU School of Medicine and a Massey researcher, he and his colleagues are encouraged by recent laboratory findings that implicate a new chemoprevention gene therapy (CGT) for preventing and treating pancreatic cancer.
They have shown that an innovative approach of combining a dietary agent with a gene-delivered cytokine effectively eliminates human pancreatic cancer cells in mice displaying sensitivity to these highly aggressive and lethal cancer cells.
Cytokines are a category of proteins that are secreted into the circulation and can affect cancer cells at distant sites in the body, including metastases. The cytokine used in this study was melanoma differentiation-associated gene-7/interleukin-24, known as mda-7/IL-24.
“Our hypothesis was that certain nontoxic dietary agents that had the ability to promote reactive oxygen species would break down pancreatic cancer cell resistance to therapy following administration of mda-7/IL-24 and be safe for human use,” Fisher said.
“We are very excited at the prospect of this chemoprevention gene therapy as a means of both preventing and treating pancreatic cancer, and it has significant potential to move rapidly into human clinical trials in the next few years.”
The dietary agent, perillyl alcohol (POH) was combined with mda-7/IL-24, which is already used in other cancer treatments. POH is found in a variety of plants, including citrus plants, and has been well-tolerated by patients who have received it in clinical studies.
The results indicated that the CGT approach not only prevented pancreatic cancer growth and progression, but it also effectively killed established tumors, thereby displaying profound chemopreventive and therapeutic activity.
The findings were published in the Molecular Cancer Therapeutics journal. Fisher’s research was supported by the National Institutes of Health and the Samuel Waxman Cancer Foundation.