From the start of the VA’s cancer research program – the organization’s first centrally funded research laboratory was established in Hines, Illinois, in 1932 – its investigators have contributed to the world’s knowledge of how to prevent, detect, and treat cancer. VA researchers were among the first to identify, in the 1940s, the link between smoking and lung cancer; they also developed the nicotine patch, discovered the colonoscopy as a superior screening tool for colon cancer, conducted some of the first studies measuring the effects of radiation on cancer cells, and established that careful observation is as effective as invasive surgery in treating early-stage prostate cancer.
“Cancer” is a general term for more than 200 different diseases that occur when the body’s cells suffer damage to their genetic coding (DNA), start to grow out of control, and sometimes invade and destroy other body tissues. Among VA patients, the five most commonly diagnosed cancers are prostate, lung, colorectal, genitourinary (i.e., kidney and bladder), and skin cancers.
“Roughly half of the VA patients who are seen in VA medical schools or medical centers are over 65,” he said. “And of course as a person gets older, cancer becomes a growing problem – aging is a risk factor, if you will, for cancer. So having a very active and strong research program supports the VA’s health care for older veterans.”
VA cancer researchers – many of them practicing physicians at VA health care facilities – conduct a broad range of basic science, translational, and clinical studies, including studies aimed at improving the quality of and access to VA cancer care. According to the cancer research program Portfolio Manager and Senior Scientific Officer Dr. Ralph Paxton, the research program is tailored to support the care of the VA’s 40,000-50,000 cancer patients. “Roughly half of the VA patients who are seen in VA medical schools or medical centers are over 65,” he said. “And of course as a person gets older, cancer becomes a growing problem – aging is a risk factor, if you will, for cancer. So having a very active and strong research program supports the VA’s health care for older veterans.”
Several decades’ worth of studies have allowed physicians to treat primary tumors, if they are detected early enough, with increasing success through combinations of surgical, chemotherapeutic, and radiological interventions. For many patients, however, these primary tumors have already metastasized – and metastatic cells, for reasons not yet understood, are much more difficult to treat or kill than primary tumor cells. “And to compound that problem,” said Dr. Alan Wells, the VA physician who directs the clinical laboratories at the University of Pittsburgh Medical Center, “the metastases often are cryptic. We don’t know that they’ve metastasized yet.” Many metastatic cells revert to a period of dormancy at the site of metastasis and go undetected – both by medical science and by the body’s own immune system – for an extended period before reactivating and proliferating.
For more than 20 years, the VA has funded the work of Wells and his researchers in studying metastases of breast and prostate cancers; in recent years, these studies have focused more specifically on what happens in the early stages of metastasis: “What are the things that protect [metastasized cells] when they are even not seen yet?” said Wells. “What makes them go into dormancy? And why do they then rise out of dormancy and grow into angry large metastases that end up killing our veteran patients?”
To answer these questions, VA investigators are studying metastases in human models – engineered human tissues, known as microphysiological systems, or MPS. Testing the resistance of metastases in an animal model, said Wells, would be irrelevant: “Animals don’t respond the same way to drugs,” he said. “A lot of the signals between the tumor cell and the body are very species specific.” What’s more, these signals often vary among individual people, which is why he and his team are hoping to expand the variety of tissue samples. The MPSs being used now are engineered from lung or liver metastases removed from patients during surgery; with funding from the National Institutes of Health, the team hopes to develop stem cells to the point where they can be used to build MPS tissues. “That would both be more consistent and allow us to sample a greater diversity of people,” said Wells.
Studying the mechanisms of metastasis – down to molecular analysis of primary, circulating and metastatic cancer cells – has obviously wide-ranging implications for the prevention and treatment of all types of cancer. But the discoveries being made by VA cancer researchers investigating issues that are more particular to an older population of cancer patients are no less significant.
Chief of Hematology-Oncology Dr. Matthew Rettig practices at the West Los Angeles VAMC and is a professor of medicine at the University of California-Los Angeles, studying the molecular and cellular biology of cancer cells, with an emphasis on genitourinary cancers. Some of these studies involve comparing the genome sequencing and protein makeup of metastatic and circulating cells – cells that break off from the primary tumor and enter the bloodstream – to cells of the primary tumor. If the team’s biostatistical analysis of circulating cells shows they have a similar molecular profile, it would suggest they might respond to similar therapies. “We can then analyze … over time the molecular evolution of cancers,” said Rettig, “not only their natural history but also their responses to therapies. So instead of trying to get a biopsy from a patient, which can be difficult, we can get a simple blood draw to molecularly analyze a tumor.”
Preventing Cancer in Older Patients
Studying the mechanisms of metastasis – down to molecular analysis of primary, circulating and metastatic cancer cells – has obviously wide-ranging implications for the prevention and treatment of all types of cancer. But the discoveries being made by VA cancer researchers investigating issues that are more particular to an older population of cancer patients are no less significant. At the Indianapolis VAMC, for example, the research of Dr. Jeffrey B. Travers, dermatologist and Indiana University School of Medicine professor of medicine, has shown that older skin handles sunlight differently – its cells are more likely to suffer irreparable DNA damage, which can begin the chain of events that result in skin cancer.
“We’ve shown that this difference is due to fibroblasts in the skin,” said Travers. “As they age, they make less of a hormone called IGF-1.” Fibroblasts play a critical role in wound healing; the IGF-1 (insulin-like growth factor 1) they produce will decide the fate of keratinocytes above them that receive DNA damage from sunlight that they cannot repair. In younger individuals whose fibroblasts make adequate amounts of IGF-1, these UV-damaged keratinocytes are not allowed to proliferate. However, in older individuals, the lack of IGF-1 in the skin allows UV-damaged keratinocytes to proliferate, forming precancerous actinic keratoses or squamous cell carcinomas. The result is that for older patients, relatively small amounts of sunlight can predispose to actinic neoplasia, which are the most common types of cancers found in veterans. While non-melanoma skin cancer is rarely lethal in the general population, mortality due to squamous cell carcinomas in immunosuppressed populations such as solid organ transplant populations can be significant.
Travers and his colleagues have discovered two means of stimulating the fibroblasts of older patients to produce more IGF-1: first, dermabrasion – literally roughing up a localized area of skin with a sandpaper-like abrasive – and also fractionated lasers, which pierce tiny holes in the skin to stimulate repair. “We don’t anticipate using lasers to treat the average patient who has non-melanoma skin cancers,” said Travers. “But for patients who have had multiple squamous cell carcinomas, and who are also immunosuppressed, I think it would be a wonderful thing. And to me it would seem like a very simple type of therapy, because there is an abnormality in how they respond to sunlight that we can repair.”
In Texas, Dr. Rhonda Souza, a Dallas VAMC physician and professor of medicine at the University of Texas Southwestern Medical Center, is part of a team that has launched basic and clinical studies looking into the continued susceptibility of patients with Barrett’s esophagus – an abnormal change in the cellular makeup of the lower esophagus – to the formation of esophageal adenocarcinoma, an often deadly cancer.
Barrett’s esophagus, in turn, is strongly associated with gastroesophageal reflux disease (GERD) – a condition caused by the backwash of stomach contents into the esophagus. GERD is a treatable condition, most often with the group of drugs known as proton-pump inhibitors (PPIs), which block the release of acid by cells in the stomach – but the incidence of esophageal adenocarcinoma has increased steadily in recent years despite the widespread availability of these acid-suppressive treatments.