Dr. Corey Casper studies the epidemiology, biology, and treatment of infection-related cancers primarily in Uganda, a global hot spot for such cancers. He contributes to the HIV+ Tumor Molecular Characterization Project (HTMCP), a project developed by the Office of Cancer Genomics (OCG) and Office of HIV and AIDS Malignancies (OHAM). The goal of HTMCP is to understand genetic differences between same tumor types in HIV positive and negative individuals, thereby allowing specifically tailored disease treatment. In this interview, Dr. Casper talks about his research background, the latest research in HIV-associated and other infection-related cancers, and how studies like HTMCP have the potential to improve cancer diagnosis and treatment throughout the world.
How did you first become interested in infection-related cancers?
I went to the Weill Cornell Medical College in New York City in the early 1990s at the height of the HIV epidemic, before the advent of antiretroviral therapies. Weill Cornell Medical College was part of the New York Presbyterian Hospital, which probably had several hundred HIV-infected patients on any given day during that time. A tremendous number of these patients had Kaposi’s sarcoma (KS), a previously rare tumor. It was a highly visible manifestation of the HIV epidemic. At the time, we had no idea what caused it, and why it was so much more common in people with HIV.
Several years later, it was discovered that an infectious agent called human herpesvirus 8 (HHV8) causes KS. I found this interesting and wanted to understand how this specific virus causes this cancer. In 2000, I started a Masters in Public Health (MPH) and an Infectious Diseases fellowship at the University of Washington and the Fred Hutchinson Cancer Research Center (FHCRC) to study this problem collaboratively with Larry Corey, the head of the Infectious Disease Division and now President and Director at FHCRC.
How did you go from studying herpes viruses in Seattle to studying infection-related cancers in Uganda?
In the late 1990s, KS was still fairly prevalent in Seattle and many other cities in the US. However, by the time I began my research fellowship, KS was becoming increasingly rare due to the widespread use of antiretroviral treatment. There were only five new cases diagnosed in Seattle in 2000 and similar reductions in burden throughout the US. Unfortunately, KS was still common in Sub-Saharan Africa, where incidence of untreated HIV infection remained very high. Uganda, in particular, proved an ideal candidate to study the etiology of infection-related cancers. Not only does Uganda have a high infection-related cancer burden, it also has a well-established cancer research institute (Uganda Cancer Institute) and a comprehensive cancer registry.
The Uganda Cancer Institute (Courtesy of Dr. Corey Casper)
As I learned more about the cancer trends in Uganda, I discovered that cancer cases in Uganda are more frequently associated with infection than in many other parts of the world. Six out of the 10 most common cancers in Uganda are caused by an infectious disease, as compared to one out of 10 in Seattle. The reason for this discrepancy was largely unknown, and I was very intrigued by it. Consequently, I decided to expand my focus from the study of KS etiology to the broader relationship between infections and cancer.
What is the goal of HIV+ Tumor Molecular Characterization Project (HTMCP) and what types of tumors will you study?
HTMCP aims to identify mutations and altered pathways in HIV-associated cancers that may respond to therapy. To do so, researchers will compare the molecular profiles of the same tumor types from HIV-positive and HIV-negative cancer patients. The three cancers being studied in HTMCP are cervical cancer, lymphoma, and lung cancer.
With HTMCP, there is a unique opportunity to compare the genomics of the three tumor types in Uganda with those in the US to determine if the underlying biology is different. Based on differences in clinical presentation of tumors between these locations, I anticipate that the biology will not be identical. Some of the tumors seen in Uganda are more aggressive and more phenotypically extreme than their counterparts in the US. Studying extreme manifestations of HIV-associated cancers may be useful when trying to identify pathways that cause cancer and/or may be therapeutically targeted. The factor causing the extreme presentation could be more common or more dramatically up-regulated than in milder forms of the disease, making it easier for researchers to find the molecular causes of that cancer.
Interestingly, this study will also give us an opportunity to investigate the genetics of HIV-associated lung cancer in non-smokers. Such studies are difficult to carry out in the US because, unlike in Uganda, a very high percentage of HIV-infected individuals in the US are smokers.
Can you make comparisons between Uganda and the US in terms of differences in HIV-associated cancer burden?
The prevalence of HIV is probably 20 to 30 times higher in Uganda and other Sub-Saharan African countries as compared to the US, making HIV-associated malignancies a greater burden in Uganda in general. Additionally, the spectrum of cancers varies between these two countries. AIDS-defining cancers (e.g., KS, certain types of lymphoma, and cervical cancer) remain the overwhelming majority of cancers among HIV-positive patients in Uganda. This trend mirrors the US epidemic circa 1995, right before antiretroviral therapies were introduced. At that time, almost all of the cancers in HIV-positive patients in the US were the “AIDS-defining malignancies.” Now, with more availability to antiretroviral therapies, “non-AIDS defining cancers,” such as liver, anal, and lung cancer, have become much more common in HIV-positive patients in the US.
This difference in the proportions of HIV-associated malignancies between these two countries may be partially explained by the fact that HIV is diagnosed at a much later stage and treatment is less accessible in Uganda, as compared to the US. However, it is still unclear if more widespread use of antiretroviral therapies in Uganda will produce a change in prevalence of the cancer types seen in HIV positive patients, similar to that which occurred in the US. Interestingly, we haven’t seen any such change yet, even though over 40% of Ugandans living with HIV have access to treatment.
What factors contribute to the increased incidence of cancer in HIV-positive individuals? Also, how do antiretroviral therapies affect incidence?
A weakened immune system caused by HIV infection is one factor. Highly active antiretroviral therapy (HAART), which helps maintain the function of the immune system by decreasing HIV replication, has reduced the incidences of certain cancers caused by oncogenic viruses. For example, HAART has been very effective at reducing rates of lymphoma and KS, two “AIDS-defining cancers.”
There is also mounting evidence suggesting that a small amount of HIV replication, independent of HIV-mediated immunosuppression, increases the risk of cervical, anal, lung, and certain other cancers. Antiretroviral therapy in HIV-positive patients has not reduced the incidence of these cancers. With lung cancer, where CD4+ T-cell count and functional immunity are not clearly associated with a greater risk, it makes sense that HAART would be less effective. For cervical and anal cancers, the relationship is less clear.
To complicate matters, some cancers, like Hodgkin lymphoma and inflammatory breast cancer, have actually increased in the HIV-positive population with HAART. So, the impact of HIV infection and antiretroviral treatment on cancer incidence may partially depend on the relative contribution of inflammation and infection to a given cancer. In this way, HIV infection may be very useful for informing us about the different pathogenesis of each malignancy.
Going beyond the study of HIV-associated cancers, what else can genomics reveal about infection-associated malignancies?
Ninety percent of the people in the world are infected with Epstein Barr virus (EBV), which is the cause of a number of different cancers. However, less than 1% of the global population actually gets one of those malignancies. Moreover, where a person lives seems to dictate the type of malignancy that develops. An adolescent in the US infected with EBV will most likely develop Hodgkin’s lymphoma, while that same virus predisposes children in Southeast Asia and Uganda to nasopharyngeal carcinoma and Burkitt lymphoma, respectively. It is likely that the underlying genomics and immunogenetics of the host play an important role in why these cancers have different incidences and clinical manifestations in different places. We can use genomics to compare different tumor types caused by the same virus to investigate this possibility.
What progress has been made and what is the promise of research projects like HTMCP moving forward?
There have been and still are significant challenges to studying HIV-associated malignancies in Uganda, but there are also real advantages. Uganda has an incredible variety and number of HIV-associated cancers, which provides a great opportunity for learning more about the genomics of these tumors and how they may differ from those in HIV-negative individuals. We have spent the last eight years building an infrastructure in Uganda for studying these malignancies, and I think we are at the point where our efforts are starting to make meaningful improvements in patient care.