UAB: Comprehensive Cancer Center

The human papillomavirus (HPV) is so tiny that its size is measured in nanometers. But its impact is immense.

HPV causes the vast majority of cervical cancers, which are the second-leading cause of cancer death among women worldwide, killing more than 286,000 each year.

But HPV has also inspired an array of research initiatives and the development of potential new treatments at the UAB Comprehensive Cancer Center. And in turn, these efforts have led to a landmark $11.5-million Specialized Program of Research Excellence (SPORE) grant from the National Cancer Institute (NCI).

One-of-a-Kind Award
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University received the highly sought SPORE award for its collaboration with researchers at the UAB Cancer Center and the University of Colorado at Boulder. Because of its successful and well-established programs in cervical cancer research, UAB will play an integral role with these university partners for this five-year grant - the only cervical SPORE in the United States.

The UAB Cancer Center has collaborated with Johns Hopkins on various research projects related to cervical cancer for several years. The two institutions decided to join forces for the SPORE, which was already held by Johns Hopkins.

“This is a partnership we’ve been cultivating for the past four years,” says Edward Partridge, M.D., director of the UAB Cancer Center and one of the SPORE’s principal investigators. “Our research programs in this area nicely complement those at Johns Hopkins. We’re excited about the opportunities ahead.”

The NCI’s SPORE programs are highly competitive and prestigious grants designed to quickly and safely move research findings from the laboratory bench to the patient bedside. The UAB Cancer Center has long been recognized as a leader in this area of translational research, currently holding or having held SPOREs in breast, ovarian, brain and pancreatic cancers. At one time, only three other institutions in the United States equaled or surpassed the number of SPOREs held by the Cancer Center.

A Closer Look at Cervical Cancer
HPV causes the vast majority of cervical cancers. Of the more than 120 types of the virus, 15 are classified as high-risk because they often cause cervical cancer. Two of those 15—known as HPV 16 and HPV 18—cause approximately two-thirds of all cervical cancers.

HPV is extremely common, and most adults are exposed to it in some form during their lifetimes. In most cases, the body’s immune system fights off the virus, and the infection clears up on its own. In other cases, the virus lingers and, under certain conditions, leads to cervical cancer.

The cervix, the lower part of a woman’s uterus that connects the body of the uterus to the vagina, includes the endocervix—the part closest to the uterus—and the ectocervix—the part next to the vagina. Most cervical cancers start in the “transformation zone” between these two areas. Squamous cell carcinoma and adenocarcinoma are the two main types of cervical cancers. About 80 to 90 percent of all cases are squamous cell carcinomas, which arise from the squamous cells covering the surface of the exocervix. The remaining 10 to 20 percent are adenocarcinomas, which develop from gland cells of the endocervix.

Building a Better Vaccine
The UAB Cancer Center was one of many institutions across the country involved in the trials that that led to the approval of Gardasil®, the first-ever HPV vaccine, by the Food and Drug Administration. Preventing HPV infection can mean preventing cervical cancer, says Warner Huh, M.D., UAB gynecologic oncologist and Cancer Center associate scientist, but he adds that there is room for improvement.

“Gardasil is a significant advancement that works great, but there are some limitations associated with it,” explains Huh, who was involved with the UAB trials of the drug. “One issue is that it only protects against two specific types of HPV—16 and 18. Because of that, women have to continue with their Pap smear screenings. The other is that Gardasil is expensive—about $120 per dose, with three shots required for the full vaccination. Our goal is to find a vaccine that protects well, but is also affordable.”

This is where the cervical SPORE may make its biggest impact. The program includes four projects investigating alternative HPV vaccines - three of which will be tested at UAB.

In the first project, researchers will investigate a vaccine that has a slightly different makeup. While Gardasil® works like most vaccines by using weakened HPV viruses to trigger an immune response, the new vaccine—developed at Johns Hopkins and produced by India’s Shantha Biotechnics Ltd.—uses a specific protein found in many HPV types. Consequently, the vaccine may garner an immune response from all 15 cancer-causing HPV types. Another key benefit is that it is inexpensive—only around $3 per dose. The trials of this vaccine will be conducted exclusively at UAB and should begin by early 2010. Principal investigators are Dr. Huh and Richard Roden, Ph.D., at Johns Hopkins.

The second vaccine-related initiative actually involves a component of Gardasil and could be a major breakthrough for preventive health care in developing nations, Dr. Huh says. “Vaccines generally must be refrigerated in order to work,” he explains. “In developing countries or impoverished areas where there is no electricity, you obviously can’t do that, which makes mass vaccination almost impossible.” This project will study a heat-stable vaccine that would require no refrigeration and would not biodegrade. Principal investigators are Drs. Huh and Roden, along with Robert Garcea, M.D., at the University of Colorado at Boulder.  

Embedding Immunity
The other two projects in the SPORE involve immunotherapeutic interventions, which have been used to study many different types of cancers. The first will focus on women with pre-invasive disease of the cervix and will be conducted exclusively at Johns Hopkins.

The second project will take place at UAB—and Dr. Huh finds it particularly exciting. “Cervical cancer is unique because it has specific HPV sequences that are found in all cervical cancers,” he says. “Having a unique target like that is not the case in most cancers.” Immunotherapy can help researchers hit that target. However, most immunotherapy injections are given into the muscle—and many of the cells that would trigger a more powerful immune response are located in the skin, well above where a needle releases a drug. So in this project, Dr. Huh and his team, which includes researchers at Johns Hopkins and UAB Division of Gynecologic Oncology director Ronald Alvarez, M.D., will be using a device known as a “gene gun” to administer a DNA compound bound to microscopic gold particles. These particles embed in the skin, similar to a tattoo, thus increasing the level of immune response compared to a standard injection.

“Not only are we looking at a therapy that has shown great promise in the lab, but we’re also looking at a unique way to administer it,” Dr. Huh says. “This is the only trial of its kind in the world.”

Protecting Alabama and the World
All four of the SPORE projects will go straight into clinical trials within a year or two of implementation, Dr. Huh says. If they are successful, particularly the vaccine trials, the impact could be enormous.

Many of the women who suffer and die from cervical cancer live in developing countries where adequate screening and medical care are not available. Therefore, the effects of a vaccine that protects against all cancer-causing HPV types and is affordable would be particularly significant.

“If such a vaccine were implemented throughout an entire country, an argument could be made to stop screening altogether, making it a cost-effective and successful way to prevent cervical cancer,” Dr. Huh says.

The number of cervical cancer cases in the United States is not nearly as high as in other parts of the world—11,270 cases will be diagnosed nationally in 2009, and about 4,000 women will die from the disease. Alabama, however, has one of the highest per capita rates of cervical cancer in the nation. This is due in large part to the state’s many rural and impoverished areas where residents do not have access to Pap smear screening or early treatment.

An effective and affordable vaccine would make huge strides in addressing this problem, Dr. Huh says. “It’s exciting to create a vaccine with the possibility of giving it to a woman as a child and telling her she’ll never need a Pap smear,” he says. “It would dramatically reduce the rates of invasive cervical cancer in any nation.

“At the Cancer Center, we’re doing multiple things that no one else in the world is doing,” Dr. Huh adds. And thanks to the SPORE, “our breadth of cervical cancer research is nearly unparalleled.”