Cancer, Interrupted

From Paths of Progress 2019

By Richard Saltus

A raging wildfire was once a mere spark or a patch of smoldering tinder – easily extinguished if caught in time.

So, too, most cancers are believed to originate as single mutant cells, proliferating to form premalignant lesions or conditions in the body that aren't at that point dangerous, but may progress to become invasive, hard-to-treat tumors. The precancerous period may persist for years, and scientists are increasingly viewing this as a window of opportunity to slow, halt, or even reverse the development of cancer.

That's the premise of a new focus in the field that some are calling "cancer interception."

"Interception is the new frontier in cancer research," says Phillip A. Sharp, PhD, chairperson of the StandUp2Cancer (SU2C) Scientific Advisory Committee and a Nobel Laureate and professor at the MIT Koch Institute for Integrative Cancer Research. "Essentially, we want to find cancer at its very earliest stages and stop it before it becomes a problem for the patient."

This new focus has emerged in part, says Norman Sharpless, MD, former director of the National Cancer Institute (NCI), because efforts to prevent cancer in the entire population with some drug or supplement have been unsuccessful. Sharpless, who visited Dana-Farber in January and is now acting commissioner of the Food and Drug Administration, said, "The traditional idea that there's a drug everybody should take to prevent cancer – that notion is dying a slow death. There have been trials of aspirin, vitamin E, vitamin D, selenium, retinoids – and most of them have failed. So, the new paradigm is identifying populations" that can be targeted with various interception strategies.

Interception – the term was first defined in a scientific paper in 2011 – is gaining traction in the field. The NCI's Moonshot Initiative has funded research toward a "Pre-Cancer Atlas" to collect molecular and genomic profiles of premalignant conditions, and how they interact with their microenvironment. The goal is to discover measurable biological signals, or biomarkers, in premalignant conditions that can help predict which ones are likely to progress to invasive cancer and which ones probably won't.

"It's fair to say that for a subset of cancers, at least, there does seem to be a precancerous or premetastatic state where there is a theoretical opportunity to change the course of the disease," says Matthew Yurgelun, MD, a physician in the Dana-Farber centers for Gastrointestinal Cancer and Cancer Genetics and Prevention.

In fact, some forms of cancer interception are already routine. Colonoscopy screening and removal of precancerous intestinal growths called polyps is estimated to reduce deaths from colorectal cancer by 50% in patients considered to be at higher-than-average risk for the disease. Other interception practices include removing precancerous skin growths before they develop into skin cancer or using Pap smears to detect abnormal cells on the surface of the cervix that can be eradicated before they become cancerous.

Cancer develops from a normal cell that undergoes genetic changes and spawns a clone of malignant cells. The goal of interception is to block that process at some point before it becomes harmful.

Precision, Prevention, and Early Detection

In a 2018 report published in Cancer Discovery, Yurgelun, Timothy Rebbeck, PhD, and Judy E. Garber, MD, MPH, of Dana-Farber made a case for what they call precision, prevention, and early detection, or PPED.

Rebbeck, associate director for equity and engagement at Dana-Farber/Harvard Cancer Center, explains that cancer prevention strategies can be thought of on three different levels. Policies aimed to reduce cigarette smoking or encourage HPV vaccination can reduce cancer risk in the general population; other strategies such as frequent screenings are targeted to specific high-risk groups, like heavy smokers or individuals with a family history of cancer. On the third level, says Rebbeck, "we can think about using molecular and biologically based mechanisms to achieve precision prevention."

For example, he says, we can design interventions for individuals who carry an inherited cancer risk mutation, such as Lynch syndrome or the BRCA breast and ovarian cancer mutations, or individuals who have been diagnosed with a precancerous lesion.

Along with population-based measures like smoking cessation, scientists are weighing molecular “precision prevention” strategies to reduce cancer risk for individuals, says Timothy Rebbeck, PhD.

SU2C first publicized interception efforts in 2017, when it announced – along with the American Association for Cancer Research (AACR) – four interception Dream Teams aimed at two aggressive forms of cancer, pancreatic and lung.

The pancreatic cancer team includes several Dana-Farber investigators, including Yurgelun; Sapna Syngal, MD, MPH, director of research in Dana-Farber's Center for Cancer Genetics and Prevention; Garber, director of the Center for Cancer Genetics and Prevention; Brian Wolpin, MD, MPH, director of the Gastrointestinal Cancer Center, and Jill Stopfer, MS, LGC, associate director for Genetic Counseling. The team's goal is to find a way to intercept pancreatic cancer in high-risk patient groups.

In the first phase of the project, Syngal and her group are leading the GENERATE Study (GENetic Education Risk Assessment and TEsting), aimed to increase the use of genetic testing by families of pancreatic cancer patients who have a mutation in pancreatic cancer predisposition genes. Individuals who are found to carry such mutations will be offered enrollment in studies aimed at pancreatic cancer interception and early detection.

The current state of the art is periodic MRI-based imaging and endoscopic ultrasound to identify early pancreatic cancers or "worrisome" precancerous lesions that may be removed surgically, says Yurgelun. However, unlike snipping out precancerous intestinal polyps during a colonoscopy, surgery to remove precancerous lesions in the pancreas is a major, complex procedure with a significant risk of complications, so it is undertaken only if the lesions are considered at very high risk of progressing to pancreatic cancer, Yurgelun says. This highlights the need for more precise, less invasive methods of cancer interception. Along these lines, researchers in the SU2C project will try to develop and test a vaccine to block the progression of precancerous pancreatic lesions.

Preventing Progression

Another interception project got a start in April 2018, when SU2C announced a $10 million award to a Dream Team co-led by Dana-Farber oncologist Irene Ghobrial, MD, to improve the treatment of multiple myeloma, a cancer of white blood cells called plasma cells. Rebbeck is also a member of the team. Myeloma develops from the precursor conditions MGUS (monoclonal gammopathy of uncertain significance) or "smoldering" multiple myeloma (SMM).

Dana-Farber oncologist Irene Ghobrial, MD, heads the new Center for the Prevention of Progression to monitor and treat people with "precursor" conditions that may progress to blood cancers.

Currently, it is unclear whether someone with MGUS or SMM will progress to full-blown multiple myeloma. "We tell people with precursor conditions that we will 'watch and wait' until it turns into multiple myeloma, with multiple tumors that potentially can cause organ damage. We want to change that so that we can act before damage occurs," says Ghobrial.

The team will follow those with precursor conditions and use the samples to search for biomarkers to help predict those with a high risk of progressing. By analyzing blood samples from about 50,000 people, the team aims to better understand the molecular and immune factors that lead to disease progression and establish effective interception strategies.

Ghobrial is also leading Dana-Farber's new Center for the Prevention of Progression, a first-of-its-kind clinic where patients with blood cancer precursor conditions will be monitored, treated, and counseled. Researchers are leading several clinical trials of novel agents and immunotherapies for patients with MGUS or SMM to determine if they can help prevent disease progression.

Clinic specialists will also see individuals diagnosed with CHIP (clonal hematopoiesis of indeterminate potential), a new diagnosis recently characterized by Benjamin Ebert, MD, PhD, chair of Medical Oncology at Dana-Farber. People with CHIP – which is increasingly common at older ages – don't have disease symptoms, but their blood harbors mutant clones that create an increased risk of developing leukemia and other blood cancers, as well as increased mortality from stem cell transplantation and from cardiovascular disease, for reasons still being investigated.

"The number of people with precursor conditions is growing, and it will continue to grow as the population ages," says David Steensma, MD, clinical director of the new center. "It is clear that CHIP raises the risk of cardiovascular death as well increasing the risk of MDS and leukemia, and MGUS can lead not only to myeloma but also to a variety of renal, dermatological, and immunological conditions. There are now tools that may prevent complications that deserve testing."

Focus on Lung Cancer

Because of the large burden of lung cancer and its high mortality, much effort has gone into early detection and treatment of the disease. Since 2013, based on studies carried out in the early 2000s, screening with low-dose CT scans has been recommended for adults ages 55 to 80 who have at least a 30-pack-per-year smoking history, and who currently smoke or have quit within the past 15 years.

Matthew Yurgelen, MD, is involved with a study aimed at increasing the use of genetic testing as a means of early detection and interception in pancreatic cancer.

However, this screening strategy has not been widely adopted thus far. One drawback is that the scans often detect lesions known as nodules that can't clearly be determined to be benign or malignant. This can lead to repeat scans, biopsies, and even potentially unnecessary surgery. Researchers are intensively looking for biomarkers, which could be detected or measured noninvasively, as with a blood test, that could help point the way to more confident diagnosis and prevent overtreatment.

Identification of one such potential biomarker – which also might be a target for preventing precancerous growths or early lung cancers from progressing – was reported in January 2019 by a team at the University of California in Los Angeles. The biomarker is a protein called SGLT2, one of several proteins that transport glucose into cells. The researchers found that SGLT2 was specifically expressed in premalignant lung nodules and early stage tumors. The studies, which so far have been performed only in mice, also showed that treatment with a drug that blocked SGLT2 in models of lung cancer reduced tumor growth and modestly prolonged survival.

The findings "provide clues that could potentially help doctors sort out which lung nodules detected on CT scans are more likely to go on to be malignant lesions and which ones don't need any further follow-up," says Bruce Johnson, MD, Dana-Farber's chief clinical research officer and a lung cancer specialist. However, he noted, the effects of blocking SGLT2 in the animal lung cancer models were not striking "and are still a long way from being applied to altering the growth of human lung cancers."

With these and many other biomarker studies, and the funding of work toward a precancer atlas to increase understanding of how premalignant states progress to cancer, researchers hope to broaden the application of interception strategies and reduce the number of patients who go on to develop cancer.