Working Group 7: The Biology of Aging and Cancer

Speaker:
William B. Ershler, M.D., Institute for Advanced Studies in Aging and Geriatric Medicine, Washington, D. C.

Co-Chairs:
Harvey J. Cohen, M.D., Duke University Medical Center
Derek Raghavan, M.D., Ph.D., University of Southern California School of Medicine

Introduction

Recent advances in the scientific understanding of the associations between aging and the development of cancer have facilitated the convergence of research perspectives to identify the molecular alterations in carcinogenesis that are related to the aging process. Common scientific perspectives of biological gerontology and oncology include the following:

1. Regulation of cellular proliferation and expression of oncogenes and tumor suppressor genes;
2. Telomere length and telomerase;
3. Free radical-induced protein and nucleic acid damage, and regulation of apoptosis; and
4. Immune function and response, such as senescence, surveillance, and enhancement.

Refined technologies and key research achievements in the biology of both aging and cancer in these and other areas hold promise for enhancing the knowledge base on the relationship between aging and the natural history of the major tumors—colon, rectum, prostate, pancreas, lung, bladder, stomach, and breast—for which peak incidence and mortality rates occur in the older population. The aging/cancer relationship is well recognized but not well characterized.

Research on the biology of aging and cancer is clinically important. Stratification of the biological characteristics of tumors with age may reveal which aspects of tumor biology and tumor growth vary in different age groups. The age-related factors that contribute to tumor growth could provide insights that could lead to tailored therapeutic approaches.

The physiologic and other disease conditions of the aged host need to be determined individually to optimize treatment selection. For example, older breast cancer patients are more likely to have estrogen/progesterone-receptor-positive tumors and less abnormal p53 expression than younger patients.

The working group noted that older patients with acute myelogenous leukemia are more likely than younger patients to present with myelodysplasia, have unfavorable cytogenetic profiles, and exhibit inherent drug resistance; they are also less likely to achieve remission. The cytogenetic and molecular genetic subtypes of acute leukemia differ in younger and older persons, and differences in epithelial tumors produce a range of biochemical and molecular changes in older persons, resulting in the vastly different clinical behaviors of these tumors in older and younger patients.

Research Questions

In his introductory remarks, Dr. William B. Ershler posed three questions that were later used to guide discussion in the working group. Dr. Tony Murgo of NCI introduced a fourth, related question in the plenary discussion.

1. Why is cancer more prominent in older persons?
2. Is cancer different in younger and older hosts?
3. Should cancer be treated differently in younger and older hosts?

These questions prompted consideration of the seed versus soil hypotheses. According to the seed hypothesis, tumor cells from older individuals are different from those of younger individuals; according to the soil hypothesis, the fundamental features of senescent hosts favor (restrained or increased) tumor growth.

4. What can we learn about the biology of cancer in the elderly that can be applied to cancer research and cancer treatment in general?

Few data exist to substantiate definitive responses to these questions, but among the theories to explain increased cancer with age are the following:

• Increased time required for cancer development (mutational load),
• Increased susceptibility of cells to carcinogens,
• Decreased ability to repair DNA,
• Dysregulated cellular proliferation, and
• Decline in immune surveillance.

Cancer Center Role

The NCI-designated cancer centers are in a position to create a critical mass of multidisciplinary professionals with expertise in the biology of aging and of cancer. An interactive network of investigators with appropriate resources and technology could catalyze research efforts to elucidate the relationship between aging and cancer in biology. An infrastructure to increase progress in assessment and intervention in regards to cancer in older persons through detection of premalignant disease, early diagnosis of malignant disease, and optimal treatment is developing (e.g., NIA is supporting studies directed at the aging/cancer interface in the Cancer and Leukemia Group B and Southwest Oncology Group).

A consortium of cancer centers could be developed for successful grant applications to:

1. Target cancer centers (those with specific laboratory/clinical expertise and/or access to population bases) and the NIA Claude Pepper and Nathan Shock centers to develop alliances for age-relevant cancer research on specific tumors, and define the minimum requirements for these consortia;
2. Target cooperative groups to conduct Phase III studies and follow-up of completed trials to address cancer survivors' late effects of treatment and conduct translational studies on older persons/patients;
3. Support infrastructure through enhancement grants or supplements for biostatistical support and data management, accrual, and labor in clinical trials, including core supplements to support specific techniques, such as polymerase chain reaction (PCR), proteomics, informatics, and imaging that require specific types of experts (e.g., statisticians, computer specialists, epidemiologists, gerontologists, and basic scientists);
4. Develop incentives that will attract both junior and senior faculty to aging/cancer research efforts;
5. Encourage junior faculty with career development grants; and
6. Encourage affiliations among cancer centers, cooperative groups, and communities, and create translational supplement awards for these partnerships to support studies on aging and cancer.

Research Priorities

1. Identify the processes and parameters of carcinogenesis in aging cells. Determine what to look for in cancer progression as it relates to aging.
   • The current cancer research focus on molecular targets should include secondary genetic changes, environmental (carcinogenic) factors, and microenvironmental (host) factors that may modulate the effects of these targets as a function of aging.
   • The overlap between cancer progression and aging should be addressed by defining the steps involved in tumor initiation, progression, and maintenance.
   • The connection between aging and microenvironments—such as the neovascularization of tumors, immune function, and hormonal control—should be examined, and processes such as oxidant stress and cell death should be considered.
   • Epigenetic mechanisms, such as methylation and multiprotein complex modulation of gene expression, should also be examined.
2. Characterize cancers and cancer cells of the major tumors that are common in older persons. Determine whether the same types of cancer manifest themselves differently in older and younger hosts.
   • How cancers of the same subtype differ between older and younger hosts should be determined. Models exist of differences in cancer in older and younger persons. For example, the cytogenetics, molecular genetics, and subtypes of leukemia differ by age, and breast cancer and sarcomas differ in histology, cytogenetics, and tumor sites. Mesenchymal-derived tumors (melanoma, sarcoma, germ cell, hematologic malignancies) behave differently than epithelial-derived tumors in older patients. The constitutive factors that are altered with age (soil hypothesis) and the factors that make tumors different in older persons (seed hypothesis) should be assessed.
   • Human studies that include appropriate controls should be conducted in association with the NCI clinical trials cooperative groups. Differences in the treatment of older cancer patients and their low participation rates in clinical trials currently make it difficult to assess their treatment response. Studying biological issues in the context of standardized treatment would be very useful.
   • The sequence of events in tumorigenesis and cancer progression needs to be explored. Younger and older persons may exhibit the same initiation event, but the sequence of events between that event and the malignancy may differ.
   • The epigenetic differences in older and younger hosts, such as methylation patterns that alter the regulation of tumor suppressors and oncogenes, should be investigated. Recent studies suggest that age-related changes in methylation may explain the differences in cancer.
   • Age-related treatment and outcome differences need to be explained.
   • The effects of cancer on young and old "normal" cells and tissues should be compared.
   • A comparative set of biomarkers needs to be defined. Molecular profiling of malignant and nonmalignant cells may be a useful approach. Profiles must be created to examine host and tumor factors in relation to aging and cancer progression. Issues for molecular profiling include methylation and epigenetic changes, telomere biology, whole exon sequencing, single nucleotide polymorphism identification, proteomics and genomics, gene expression microarrays, and molecular therapeutic response parameters.
   • Tumors should be characterized to examine age-related expression of molecular targets, such as tyrosine kinases. Leukemias may be easier to characterize because of tissue accessibility. Solid tumors are more difficult to characterize, but they have a higher level of heterogeneity.
3. Explore elderly populations at low risk for cancer (i.e., with an age-resistant phenotype). Identify the genetic or epigenetic changes associated with this protective phenomenon. Conversely, develop insights about why certain older cancer patients are at high risk for multiple primary tumors. Identify the key shared predisposing or protective factors for developing multiple primary tumors.
   • The efficacy of radiotherapy in elderly patients should be explored. Radiobiologic and genetic studies could contribute to the development of information on older patients, because they probably constitute the largest subset of individuals with a greater susceptibility to treatment toxicity due to (1) the inherent cellular radiosensitivity of their tumor cells or normal cells; (2) differences in cellular repair and cell kinetics, including repopulation of normal and malignant cells; and (3) differences in recruitment of normal cells into active proliferation.
   • New technologies should be used to explore old models. Mice mutagenized for other studies might be classified by age; this would make it possible to examine the ability of genes that affect the predisposition for cancer to influence aging rates.
   • New preclinical models should be examined. Animal models with long life spans should be used to generate hypotheses, taking advantage of their extensive characterization and adequate controls to facilitate translation to clinical research.
   • Tissue acquisition programs and tissue banks focused on aging/cancer studies should be developed.

Research Barriers

• Maintaining long-living animal systems is costly.
• Aging research is lengthy. Funding cycles need to be appropriate to the research endeavor.
• Solid tumors are often heterogeneous.
• Quality of clinical data varies, which is also a problem of quantity. Because of the low participation rates of older patients in clinical trials, sufficient statistically valid data are not available.
• Annotation systems differ for mice and humans.
• Translation of data from animal studies to the clinic is problematic because no transfer mechanism exists to allow the free flow of information.
• Ethnic heterogeneity is a significant barrier. For example, Latino populations have different drug resistance gene expression than non-Latino whites. Other racial variations exist in tumor growth, susceptibility, and treatment response of the elderly.