National Institutes of Health Campus
Bethesda, Maryland

The AIDS Malignancy Working Group (AMWG) was convened during the 4th International AIDS Malignancy Conference (IAMC) to facilitate brainstorming focused on identifying the major areas of research priorities in AIDS malignancies. The intent was to identify the scientific and clinical highlights of the IAMC and determine where we might want to direct our future research. Dr. Ellen Feigal provided an overview of the evolution and purpose of the AMWG. The AMWG was established in 1996 and is a multidisciplinary group that includes members from both the intramural and extramural component of NIH, researchers outside of NIH, and community representatives. The group is convened yearly to discuss the biomedical opportunities for AIDS malignancies, the clinical gaps in our knowledge, and mechanisms to move the research forward and address specific issues. Fruits of the efforts of previous AMWG meetings include:

• The yearly NCI-sponsored IAMC, to provide a forum for discussion of research in AIDS malignancies;
• The AIDS Oncology Clinical Training Program;
• The AIDS Oncology Resource Handbook, a compendium of intramural NIH and extramurally funded research projects across the US and a list of resources including the AIDS Malignancy Consortium (AMC) and the AIDS and Cancer Specimen Bank (ACSB);
• Initiatives for supplemental funding to stimulate collaborations between Centers for AIDS Research (CFAR) and Cancer Centers investigators.

After introductions around the table, Dr. Jodi Black discussed the value to AIDS research of working with international collaborators, reviewed the existing NIH mechanisms for international research, and summarized the Office of AIDS Research (OAR) International Priorities for FY2002. As HIV has a widening geographic distribution the complications of HIV including malignancies can be expected to follow new infections particularly in areas where primary treatment of the HIV is limited. Many research topics require international collaboration since some diseases are more prevalent in certain areas, Kaposi's sarcoma (KS) in Africa for example. In addition, limited access to a patient population within any single country make international collaborations attractive so studies can be completed in a timely manner. NIH mechanisms for conducting international research include both global research network programs (listing attached) and components of individual grants as well as training initiatives. These mechanisms provide piggyback potential for supplemental NCI funding for AIDS malignancy research initiatives.

The OAR has developed a set of international priorities for AIDS in FY2002 as follows:
· Nurture centers of excellence in international settings that will provide an environment for the development of true and equal partnerships between U.S. and foreign investigators. These centers will support basic research and long-term cohort studies, serve as loci for studies of efficacy of biomedical and behavioral prevention interventions, including Phase I, II, and III vaccine trials, function as training centers for investigators from the region, and serve as bridges with services.

• Conduct studies relevant to geographic areas of the world and specific populations hardest hit by the epidemic.
• Enhance translation of research results into action that will improve patient management, develop prevention programs appropriate to the setting, and effect policy changes.
• Continue to enhance training for research needs, clinical capability and for technology transfer, building bridges to services where possible.

The invited speakers then presented their overview of the research needs in the broad categories of Epidemiology and Databases; Virology, Immunology, Cancer Biology and Drug Development; and Prevention and Treatment.

PRESENTATIONS
Epidemiology and Databases

Dr. James Goedert, Chief, Viral Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute

Dr. Goedert noted that this AMWG meeting was a timely opportunity to bring together a larger group and some new members to discuss needs for AIDS malignancy research while the data from the IAMC was still fresh in our memories. He presented four main domains for future research.

1. What is the effect of HAART on the risk of developing NHL and KS and what are the resulting characteristics of disease? Determine the differences in clinical patterns, histopathology and molecular characteristics of lymphomas that occur in people on HAART and compare to cases in the pre-HAART era retrospectively, and to lymphomas in HIV- patients.
2. The predominant modes of HHV-8 transmission (saliva, sexual) need to be determined and the in vivo reservoirs identified. Where does the virus replicate in vivo?
3. What determines the transition from in situ to invasive disease in HPV related cancers? Immune deficiency related to HIV leads to a progression up to but not necessarily past the in situ stage. What triggers the transition to the invasive stage? A comprehensive evaluation of molecular and immunologic studies is needed to sort this out and anal cancer is an appropriate model to examine. Prevention and treatment studies can be tied into opportunities to study the mechanisms of progression and can be used to implement screening in developing countries, Africa, India, and Brazil.
4. Explain the heterogeneity in international cancer risk. HIV is associated with Hodgkin's disease, liver cancer, and leukemia in the U.S. and Europe but not in Africa. Other cancers such as childhood Burkitt's lymphoma are unaffected by HIV immune deficiency. The critical molecular lesions are occurring independently of the immune-deficiency process.

Dr. Silver noted that some of these studies might utilize samples available from the ACSB. These samples include their associated clinical data, such as anti-tumor and anti-retroviral regimens.

Dr. Valerie Beral, Professor, Cancer Epidemiology Unit, Imperial Cancer Research Fund, University of Oxford

Dr. Beral noted that cervical cancer is the most common cancer in developing countries and this is an important area for research. What is the excess of cervical cancer in HIV+ individuals in developing countries?

There is a need to develop a system to link databases in developing countries and to develop large enough cohorts to make linkages between AIDS cases and cancer cases. Dr. Beral noted that approximately 25% of the population in developing countries are HIV+ and thus suggested that more information about cancer in the HIV setting might be available from cancer registries in these areas. Dr. Sitas noted that registries cover less than 1% of the population in Africa. A prospective approach may be possible if a link can be established with ongoing studies such as the NIAID sponsored HIV Network for Prevention Trials (HIVNET). The HIVNET is a multi-center, international, collaborative research network whose mission is to evaluate the safety and effectiveness of promising interventions to prevent HIV transmission. Tapping into other studies, such as those screening for Hepatitis B virus or Hepatitis C virus may also be useful.

Virology, Immunology, Cancer Biology and Drug Development
Dr. Elliot Kieff, Professor of Microbiology and Molecular Genetics and Professor of Medicine, Harvard University.
A virologist's overall perspective may be useful here. HIV infection in much of the developing world and much of Africa is like HIV infection in the US in the early 80's before the use of anti-retroviral therapy and before we knew how to prevent or efficiently treat the opportunistic infections that occur in HIV infection. Super-imposed on this are varying components of lack of trained medical and paramedical personnel, inadequate facilities, malnutrition, parasitic infection, lack of availability of drugs to treat many of the infectious complications of HIV, and in some places extensive political and social disruption. In this setting, the greatest impact will be made by educational and other programs, which can prevent HIV infection. Second, even if only partially successful, HIV vaccine research and development could have its biggest payoff in prevention of infection in the developing world. Establishing a small number of vaccine centers to study HIV infection and the host immune response in developing countries would provide an infrastructure for subsequent vaccine studies and vaccine applications in these areas. Third, or in parallel with 1 and 2, a small number of improved health facilities need to be supported which can serve as model sites for prevention, diagnosis, and treatment of HIV and related infections and for the training of medical and paramedical and technical personnel in these areas. Fourth, cost effective expenditure of funds for HIV infected people in the developing world may be somewhat different than in the developed world and will depend on many factors including local social and political factors. High priority should be given to lower cost anti-retrovirals, anti-retrovirals to prevent mother-child transmission, milk to prevent mother child transmission, pneumocystis prophylaxis, availability of antibiotics etc as is appropriate in each setting. As the standard of HIV infection care in the developing world approaches that in the developed world, issues of the prevention and treatment of HIV associated malignancies will likely be a relatively more important problem than they are now in the developing world. At the current time, viral associated malignancies are a major burden for the developing world, not only for HIV infected people but also for normal people. KSHV and high-risk HPV infections are more common in some normal and HIV infected populations and this results in a high incidence of KS and cervical and ano-genital carcinoma. KS is an important problem in HIV infected people as well. In some populations early HIV opportunistic infection related death is common and most people do not survive long enough at the current time to make cervical and anogenital malignancy a much greater problem in HIV infected people than in the normal population. Although EBV associated malignancy is an important cause of death in late stages of AIDS in the developed world, HAART therapy has at least temporarily reduced progression in most of the population so that the incidence of EBV related lymphoproliferative diseases and even KS is way down. Cervical and anogenital malignancies are only marginally more common in HIV infected people because of the long lag time between progression from increased virus replication to invasive cancer. The incidence of lymphoproliferative diseases, KS and cervical and anogenital cancer may increase as the length of lifetime but with reduced or absent immunity increases in those people getting HAART treatment. Hepatitis B and C are important causes of hepatocellular carcinoma in developing and developed worlds but do not appear to be more of a malignancy burden in HIV than in normal people. (HTLV-1 infection does not appear to be a more common cause of malignancy in HIV infected than in normal people). Within this overall framework, much needs to be done in viral associated malignancy research and this will have an impact on viral associated malignancy in both HIV infected and normal people. To some extent, lessons learned here will also contribute to the understanding and solution of problems of HIV prevention and treatment as well as the prevention and treatment of viral associated malignancies in normal people.
From that perspective it is important to fund research in

1. Immunity to oncogenic virus infections in normal, immune compromised and HIV infected people.
2. Ways to boost the immune response to oncogenic virus infection in normal, immune compromised and HIV infected people. Including strategies such as ex vivo expansion of cells, thymic education, etc.
3. Basic research in mechanisms by which oncogenic viruses cause malignancy by causing abnormal cell growth and survival.
4. Translational research at the basic in vitro, experimental animal, and human level in target development, small molecule drug discovery and pharmaceutical development of suitable candidates for prevention or treatment of virus associated malignancies.
5. Not all malignancies that are increased in HIV infected people are caused by known etiologic agents; some are caused by genetic or environmental factors and occur with a higher frequency in HIV infected people because a virus plays some role in the process or because normal immune function has a role in surveillance against the malignancy. For example B cell lymphomas without EBV or KSHV are more common in HIV infected people and in the aging normal population and T cell surveillance may be the problem here. Contemporary micro-array approaches to transcriptional profiling and genomic analysis may facilitate the identification of the underlying processes.
6. Surveillance of HIV associated malignancies for new oncogenic viruses should continue at some level since they would be expected to be found more frequently in malignancies in immune compromised patients.
7. Animal models for pathogenesis are a key tool to transition between basic research and the identification of targets for chemotherapy and for prevention and immunotherapy work. Models of both infection and cancer are needed for studies of drug development and immunoprevention.
8. Interactions between virologists, epidemiologists, and a strong clinical backup need to be fostered. If international centers were funded than they should consist of these components along with strong links to databases.

Dr. Richard Ambinder, Professor, Johns Hopkins School of Medicine

A variety of viral targets for gammaherpesvirus-related malignancies were discussed at the IAMC meeting. These included episomal maintenance of EBV or HHV-8; NFkB related pathways in EBV; activation of expression of viral enzymes; induction of lytic infection to kill tumor cells; and antigen targeted therapies. Studies in these areas may lead to strategies of using immune manipulations to control disease. There have also been dramatic results in the bone marrow transplant (BMT) setting using adoptive T-cell immunotherapy. Autovaccine therapies were presented at the IAMC meeting that consisted of scheduled stops in anti-retroviral therapy, thereby allowing T-cells to respond and control the virus. These results suggest a need to develop appropriate combinations of HAART, antimicrobials, chemotherapy, and immunotherapy for managing opportunistic malignancies, opportunistic infections and other complications of HIV infection in addition to controlling HIV.

Dr. Ambinder noted two additional important highlights presented at the IAMC; the use of vaccines in fighting malignancies, and the mini-transplant approach which demonstrated that immunotherapy has the potential to control hyperplasia and more aggressive malignancies. Based on these reports, it was suggested that a vaccine program in AIDS-related malignancies be a research priority. Initially, a therapeutic vaccine program to prevent recurrences needs to be developed. Many currently used therapeutic approaches to treating disease are too expensive to the developing world but vaccine approaches may be more economically exportable. The mini-transplant is a new approach to immune manipulation and this method is more tolerable than a conventional transplant in the HIV setting.

We lack basic information about the interplay between the immune system and viral-mediated cancer development. Does regression of KS after removal of immunosuppressive agents in transplant patients reflect a recovery of T-cell function? Can T-cells in that setting be shown to specifically target HHV-8 viral antigens? The same questions apply to EBV-related lymphomas. Does differential development of EBV-related lymphomas in HIV+ patients reflect differences in the host immune response or do environmental, dietary, or other infectious agents serve as cofactors that contribute to the type of malignancy that develops? Why do other viral associated malignancies, such as EBV-associated nasopharyngeal carcinoma, not associate with HIV?

Prevention and Treatment
Dr. David Scadden, Associate Professor, Massachusetts General Hospital

Dr. Scadden discussed the research needs for non-Hodgkin's lymphoma in the area of treatment and prevention.

Immunology: Using vaccines for B-cell malignancies were addressed at the IAMC. Can we vaccinate AIDS-related lymphoma (ARL) patients in the context of other treatment related to HIV infection? How can we best introduce vaccination into trials and consolidate with existing trials?

Transplantation: Transplant therapies may be applicable to NHL patients and we need to rapidly proceed with trials. The trials should be coupled to gene therapy trials and include an intensive assessment of the virologic and immunologic impact on NHL. It would be useful to try to link the AMC with investigators performing transplant studies and to efforts investigating stem cell manipulation as treatment for lymphoma. Information regarding virologic and immunologic factors in NHL could be obtained during these studies.

Areas to develop:

• Perform comparative genetic profiling of Burkitt's lymphoma versus other subsets of ARL. Results will help identify potential targets for intervention. Organ site preference of lymphoma development needs to be studied to determine why subsets of ARL occur and to identify potential surface targets, or unique cell surface molecules. Can molecular differences in organ site localization lead to identification of unique cell surface molecules useful as therapeutic targets.
• Perform longitudinal studies to evaluate host-virus interactions to help determine the steps that lead to malignancy. Molecular profiling studies can be performed using banked tissues or prospective studies can be developed. Studies of undifferentiated, immortalized but non-transformed normal B-cell cultures may help elucidate the mechanisms of transformation. Is there a mechanism that predisposes cells to undergo transformation?
• Clinical trials will become more complicated to conduct over time due to the changing epidemiology of AIDS malignancies; we should be developing a critical mass of international investigators.

Dr. Parkash Gill, Professor of Medicine and Pathology, University of Southern California School of Medicine

Dr. Gill discussed the research needs for KS prevention and treatment in the categories of anti-angiogenesis, immunology, prophylaxis, and evolution of disease.

Anti-angiogenesis: Angiogenesis plays a role in the development of KS. Can we use KS as a model for anti-angiogenesis studies? There are many new agents; how do we select and prioritize which agents to test? We need to develop parameters for laboratory and clinical evaluation and determine what parameters to measure for drug efficacy. Information on drug effectiveness using KS as a model might be translated to solid tumor therapy.

Immunology: Does HHV-8 activity correlate with disease state and can this activity be used therapeutically to monitor the effectiveness of therapy? Is there vaccine potential for this disease?

Prophylaxis: Is HAART sufficient? What are the mechanisms of HAART's effects on KS regression? We need to study HHV-8 parameters in patients on anti-retroviral therapy and compare them to parameters in patients not treated with anti-retroviral therapy. This would require an international collaborative effort.

Evolution of disease: Genetic profiling should be performed to examine changes in virus and host gene expression during the course of treatment. The genetic defects in KS need to be identified. We need a comprehensive view of the differences in KS tissue compared to normal endothelial cells. Can we incorporate viral and cellular gene alterations into therapy development and use them as outcome measures?

AROUND THE TABLE DISCUSSION

Dr Feigal suggested the discussion focus on the broad categories of research and to give examples of some of the unanswered questions. What do we need to know to move the field of AIDS malignancies forward? All AMWG members contributed to the discussion, and most of the issues could be broadly grouped into 7 general categories; International Issues, Linking NIH-Funded Studies, Mechanisms of Pathogenesis, Non-AIDS defining Cancers, Treatment and Prevention Strategies, Animal Models, and Tissue Banking.

International Issues

The prevalence of HIV is expanding in developing countries. Individuals at risk for malignancy may be higher in these areas and thus may provide a population that has the potential to benefit from future vaccine trials. We need to perform epidemiology studies in Africa where clinical outcomes of HHV-8 infection, rare in the U.S., have the possibility of being detected. Also other rare cancers such as cancer of the conjunctiva are prevalent in Africa.

There are few unanticipated cancers in the HIV+ population in developing countries. However, we know very little about the types of cancers in the Asian population and Thailand has the infrastructure to set up these epidemiologic studies.

Coordination is needed to link all of the NIH information on international studies and make it available to the scientific community. Existing international networks might provide a leveraging mechanism for NCI supplemental funding for AIDS malignancy research. Registries in Asian countries and India are needed to track the epidemic.

Patient accrual problems in the U.S. were discussed. Due to small patient numbers, we may need international collaborators for clinical trials to move the field forward in a timely manner. Dr. Kaplan gave an example of an AMC clinical trial that may take 4 years to accrue 120 patients. This lengthy process saps resources to explore other new therapies. Dr. Feigal noted that the more developed countries may help with AMC studies but feasibility issues and lack of infrastructure will make it difficult for less developed countries to participate in most clinical trials. Participation in some simpler regimes or engaging the international community in contributing tissue samples for basic research might be feasible. Dr. Krown noted that although international collaboration would be useful and interesting, the patient population does exist in the U.S. and accrual problems are mostly due to lack of appropriate referral to trials. This may be due to lack of information on the part of the primary care physician or the decision of oncologists to treat patients in their private office.

Linking NIH-Funded Studies

There is a need to develop a formal mechanism of referral and collaboration between the AMC and the other AIDS clinical trials groups [AIDS Clinical Trials Groups (ACTG) and The Terry Beirn Community Programs for Clinical Research (CPCRA)]. Dr. Duncan, NIAID, noted that he has begun working with Dr. Black to establish that link. Dr. Levine suggested hiring a person at each site specifically to link the ACTG and AMC.

The ACTG and CPCRA trials see AIDS patients who are at risk for cancer and longitudinal samples collected from at risk individuals are needed. Pre-neoplastic tissue is necessary to look for clues to cancer development. The ACTG and CPCRA combined are following approximately 6000 patients and are storing samples from case/control studies. Dr. Duncan noted there are also large European cohorts in Switzerland and France that are followed through their public health system and he would be able to supply the names of epidemiologists from those countries who might be willing to collaborate.

Dr. Schouten and Mr. Marco stressed the need for cooperation and collaboration between the Groups. They also suggested that samples from the Adult AIDS Clinical Trials Group Longitudinal Linked Randomized Trials (ALLRT) Protocol would be useful for studying pre-cancer markers; however it is unclear if outside access to these samples would be possible.

The HIVNET network was used as an example of employing an existing mechanism for multiple study purposes. HIVNET is a global prospective HIV vaccine efficacy study network that screens out the HIV+ population. These HIV+ individuals could be referred to studies seeking to gain further knowledge about AIDS malignancies. Is it possible to link HIVNET studies with HPV vaccine trials? Women recruited to HIVNET in areas where HPV related cancers are highly prevalent, such as Africa, could simultaneously participate in HPV natural history studies. Those that develop HPV related disease could also participate in HPV vaccine trials, thus the biology of HPV could be studied in the same cohort as the vaccine trials.

Perinatal transmission studies also provide an opportunity to examine preexisting infection with viruses. HIV+ pregnant women enter trials for transmission reduction and then continue to treat the infant after birth for up to 6 months to prevent transmission during breast-feeding. This provides an opportunity to prospectively follow both mother and infants for 6-9 months to assess changes in markers of viral activity or immunologic activity. Infants that convert to HIV+ can be referred to early clinical trials.

Mechanisms of Pathogenesis

Dr. Kaplan noted that an obstacle to moving the AIDS-malignancy field forward is a lack of understanding of AIDS lymphoma pathogenesis. More pathogenesis-related studies need to be encouraged. He suggested using banked samples to compare the molecular characteristics of tumors collected from HIV+ and HIV- patients perhaps by utilizing microarray technology. Dr. Scadden noted that although gene profiling is a useful tool, training in bioinformatics in the cancer area is necessary to interpret results. We need to determine the pathogenic mechanisms of non-EBV related lymphomas.

We need to know more about the genetic alterations in the pathway to lymphoma and the differences in these alterations between HIV+ and HIV- patients. The key genetic player is c-myc alterations but this occurs prior to lymphoma development so the cancer cell itself may not be the best place to begin looking for genetic changes. It might be better to examine the basic biology of the tissue prior to lymphoma development to find clues to what is driving and regulating transformation. A good place to start is the follicular center to examine the interaction of B-cells with germinal centers in the nodes. Research into the environment of the follicular centers needs to be a priority.

Dr. Offerman noted that we need to examine the relationship of genetic instability induced by viral infection for further DNA damage that leads to cancer. She suggested linking investigators studying genetic instability with virologists to accomplish this task.

Treatment and Prevention Strategies

Dr. Palefsky noted that the current NIH-funded HPV vaccine trial in Costa Rica uses a prophylactic vaccine and that a therapeutic vaccine is still necessary. This type of vaccine would couple nicely as treatment during the much-needed anal vaccine screening program. There are multiple candidates that need to be tried for precancerous dypslasia to prevent development of full cancer. At this point we have a unique historic opportunity to examine the natural history and progression of this disease prior to the screening programs being in place. Since this tumor is prevalent in the HIV- population as well, we can compare them with the HIV+ population. There is a need to develop training programs for clinicians to develop skills to assess anal intraepithelial neoplasia. Screening programs won't be available until training programs are in place. He suggested that NCI could facilitate this. Dr. Levine noted that anal screening should be a priority and that we need to look at obstacles for why women aren't being recruited to cervical screening. Dr. Palefsky is bearing the training burden right now. A U.S. training program for MD's needs to be developed and it was suggested that NCI take the initiative.

We need to determine at what level of immune impairment to start intervention. We also need to address complications in the HAART treated long-term survivor patient population.

Other questions included what is the impact of IFN-gamma on KS? Is the effect immune or viral mediated; exactly how does it work?

Explore the treatment strategy of inducing latent herpesviruses as part of the mechanism to kill tumor cells in conjunction perhaps with a thymidine kinase suicide gene method. Some natural compounds will activate viruses and NCI has a repository of compounds that could be tested. Resources for drug development exist within NCI and information can be obtained at http://DTP.NCI.NIH.gov. Access to the compounds, the NCI natural product library, and synthetic compounds in 96 well plates are available.

Non - AIDS Defining Cancer

• How do non-AIDS malignancies behave in HIV+ patients, for example, breast or lung cancer?
• Is there an increased risk of developing non-AIDS malignancies in the HAART era population? ACTG patients are living longer and non-AIDS tumors are being detected in long-term survivors.
• Is there a mechanism for follow-up of children who were treated with AZT in this country?
• What is the lifetime risk of developing tumors in HIV+ patients?
• Should we be monitoring persistent generalized lymphadenopathy tissue in HIV+ patients?

Animal Models

What needs to be done to generate appropriate animal models for AIDS malignancy research and drug screening? Models for lymphoma and trans-gene animal models for HPV in mice exist and are appropriate for drug screening studies. Are these the types of models that are needed? How do we encourage the creation of new appropriate models? Dr. Wu noted that Dr. Mary Wolpert advertised a program announcement for preclinical models in AIDS malignancies but received few responses. Dr. Cremer mentioned that he receives 2 to 3 grants per round in response to basic research and pathogenesis models. He then discussed the possibility of using SIV infected monkeys for lymphoma studies. About 5%of the SIV-infected rhesus monkeys and about 30% of SIV-infected Cynomologous monkeys develop high-grade lymphomas indistinguishable from human lymphomas. However, it takes years for the animals to develop lymphoma, most of which are extranodal and found at autopsy. Additional funds would be necessary to care for and observe the animals during this time at a cost of approximately $2000 to $3000 per year. Most of the current support is from the National Center for Research Resources. A large collection of these lymphomas is banked at Tulane. It is not yet clear if the monkey homologs of HHV-8 and EBV are involved in the lymphoma process. This is a very good model but time and expense are a major limitation. It would be useful to develop a method to forecast which animals will develop lymphomas.

Tissue Banks

Information about tissue bank resources needs to be disseminated including Standard Operating Procedures for storing and using samples. Does the Centers for Disease Control and Prevention or the Armed Forces Institute of Pathology have tissue available?

It would be useful to develop a resource book describing proper specimen collection and storage for different types of tests. For example, what types of tests can be performed on tissue blocks that have been stored for decades?

NCI is putting out an initiative to improve access to valuable specimen collections with associated clinical data to the research community.

Summary and Action Items

Gaps and roadblocks

• Lack of knowledge of basic information about the interplay between the immune system and viral-mediated cancer development.
• Lack of access to longitudinal samples, which are necessary for studies of the natural history of disease and therapeutic target identification.
• Lack of knowledge of the molecular evolution of disease
• Lack of knowledge of the basic biology, pathogenesis, genetics, and regulation of AIDS-lymphoma development
• Lack of knowledge of the natural history and progression of HPV-associated anal cancer

Resources are needed to facilitate research in the following areas

1. Epidemiology
• Develop cancer registries in developing countries
• Target the Asian population and India, where infrastructure is in place
• Target cancers that are rare in the US, for example HHV-8 related primary effusion lymphoma. The prevalence of these cancers may be higher in areas where HHV-8 is more prevalent such as Africa.
• Investigate the effect of HAART on cancer characteristics and risk, the international heterogeneity of cancer, and the life-time risk of developing cancer including non-AIDS defining cancers and primary gastric lymphoma.

2. Molecular Biology, Pathogenesis and Drug Development
• The natural history and pathogenesis of virus related cancers (EBV, HHV-8/KSHV and HPV) and the relationship to the immune system. Does virus activity correlate with disease state? Does host immune response or other cofactors determine what cancers develop?
• Models for pathogenesis and therapeutics development
• Determine the mechanisms of drug effects on disease progression
• Study genetic instability mediated by virus infection and the relationship to disease development and progression

3. Therapeutics
• Target immunotherapy, immune based treatments and stem cell manipulation as treatment for lymphoma
• Use genetic profiling and study host-virus interactions during the evolution of malignancy to identify targets and triggers of transition from in situ to invasive disease and factors involved in non-virally mediated lymphomas
• Develop a therapeutic vaccine program and consolidate vaccine trials with existing trials
• Use KS as a model for anti-angiogenesis drug studies

Additional action items

1. Training and education
• Train and educate physicians to participate in and refer to clinical trials
• Sponsor an anal cancer screening training program
• Disseminate information about tissue banks and protocols

2. Facilitate linkages
• Facilitate interactions between virologist, geneticists, clinicians, and epidemiologists
• Identify a facilitator to link all of the NIH information on international studies and make it available to the scientific community.
• Foster the development of international collaborations
• Develop a formal mechanism to link NIH-funded cooperative groups (i.e., AMC and ACTG)
• Link the AMC with investigators performing transplant studies

Summary of NIH mechanisms with leveraging potential for international research:

Fogarty International Center:
http://www.nih.gov/fic/programs/grants.html#otheropps
    HIV-AIDS and Related Illnesses Collaboration Award (AIDS-FIRCA)

     AIDS International Training and Research Program (AITRP)
     Fogarty International Centers of Research Excellence (FICORE)
     Oncology Research Faculty Development Program

Division of AIDS/NIAID:
http://www.niaid.nih.gov/research/daids.htm
    HIV Network for Prevention Trials (HIVNET)
    HIV Prevention Trials Network (HPTN) (multi-agency)
    
HIV Vaccine Trials Network (HVTN)

Division of Microbiology and Infectious Diseases/NIAID:
http://www.niaid.nih.gov/ictdr/default.htm
     International Centers for Tropical Disease Research (ICDTR)

Center on AIDS and Other Medical Consequences of Drug Abuse (CAMCODA)/NIDA:
http://www.nida.nih.gov/NIDAHome1.html
     Global Research Network on HIV Prevention in Drug-Using Populations

Division of Mental Disorders, Behavioral Research and AIDS (DMDBA)/NIMH:
http://www.nimh.nih.gov/dmdba/index.htm
     HIV/STD Prevention Trial
     http://www.grants.nih.gov/grants/guide/rfa-files/RFA-MH-99-011.html

National Institute of Dental and Craniofacial Research (NIDCR):
http://www.nidr.nih.gov/

National Institute of Child Health and Development (NICHD):
http://www.nichd.nih.gov/
     Global Network for Women's and Children's Health Research
     http://grants.nih.gov/grants/guide/rfa-files/RFA-HD-00-007.html
    International Maternal and Child Health Research and Training
     http://grants.nih.gov/grants/guide/rfa-files/RFA-TW-00-007.html

National Cancer Institute (NCI):
http://www.nci.nih.gov/
     International Network for Cancer Treatment and Research (INCTR)
     http://www.inctr.org
     A summary of NCI international activities can be found at:
     http://cancernet.nci.nih.gov/oia/master.html