Scientists are studying cancer genomes to more precisely diagnose their patients' diseases - offering hope for targeted drug treatments.
Next, he recalls, he felt ushered into “the jaws of the medical system very quickly.” He spent a couple of days meeting with a team of doctors at Beth Israel Deaconess Medical Center in nearby Boston. One of them was from a medical field he hadn’t even known existed, a pulmonary interventionist, who would perform a biopsy on the mass in his lung.
“Knowing there was a medicine for my particular type of cancer was like a weight lifted off my shoulders."
A week later he and his wife Allison returned to meet with the oncologist, radiologist, pulmonary interventionist – his medical team. They confirmed his initial diagnosis: Stage 4 metastatic lung cancer that had spread to several parts of his body. “We just sat there, stunned,” he says. “I felt like I was getting hit by a wrecking ball over and over.”
An onslaught of medical terminology about what they had identified flowed over the shocked couple, but then the medical team switched gears, he recalls. They offered hope. “They told me, ‘Hey, you’re not a smoker, so that’s good,’” Reiner says. “‘There’s a good chance that what’s driving this disease for you is actually a genetic mutation, and we have ways to understand more about what that could be through some simple testing.’”
They told him about Foundation Medicine, a company launched in neighboring Cambridge, MA, in 2009 that develops, manufactures, and sells genomic profiling assays. These are tests that, according to the company’s website, “can analyze a broad panel of genes to detect the four main classes of genomic alterations known to drive cancer growth.” With these insights, certain patients can be matched with therapies targeted specifically for the genetic driver(s) of their cancer. The company maintains one of the largest cancer genomic databases in the world, with more than 500,000 patient samples profiled, and they have more than 65 biopharma partners.
According to Foundation Medicine, they are the only company that has FDA-approved tests for both tissue- and blood-based comprehensive genomic profiling tests. One other company has an FDA-approved biopsy test, and several other companies offer tissue-based genomic profiling. Additionally, several major cancer centers like Memorial Sloan Kettering in New York and Anderson Cancer Center in Texas have their own such testing platforms.
Currently, genomic profiling is more accessible for patients with advanced cancer, due to broader insurance coverage in later stages of disease.
“Right now, the vast majority of patients either have cancers for which we don’t have treatments or they have genetic alterations that are not known,” says Jorge Garcia, MD, Division Chief, Solid Tumor Oncology, UH Cleveland Medical Center, which has its own CGP testing platform. “However, a significant proportion of patients with advanced cancer have alterations that we can tap for therapeutic purposes.”
Foundation Medicine estimates that in 2017, just over 5 percent of advanced solid cancer patients in the U.S. received CGP testing. In 2021, they estimate that number is between 25 to 30 percent of advanced solid cancer patients in the U.S., which doesn’t include patients who are tested with small (less than 50 genes) panels. Their panel tests for more than 300 cancer-related genes.
“The good news is the platforms we are developing are better and more comprehensive, and they’re going to continue to be larger data sets,” Dr. Garcia adds.
In Reiner’s case, his team ordered comprehensive genetic profiling on both his tissue and blood, from Foundation Medicine.
At this point, Reiner still wasn’t sure what genetic mutations were or how they factored into cancer or what comprehensive genomic profiling entailed. That day, though, his team ushered the Reiners into the world of precision oncology that placed him on much more sure footing to learn about and fight the specific lung cancer that had been troubling him for more than a year.
What genetic alterations were driving his cancer? Foundation Medicine’s tests were about to find out.
At the core of these tests is next generation sequencing, a DNA sequencing technology. Since 2009, this has revolutionized genomic research, according to the National Center for Biotechnology Information, because it allows an entire human genome to be sequenced within one day. Cancer genomics posits that cancer is caused by mutations and is a disease of the genome. Now, cancer genomes can be systemically studied in their entirety. For cancer patients such as Reiner, NGS can provide a more precise diagnosis and classification of the disease, more accurate prognosis, and potentially the identification of targeted drug treatments. Ultimately, the technology can provide the basis of personalized cancer management.
The detailed reports supply patients and their oncologists with extensive information about the patient’s genomic profile and potential treatment options that they can discuss together. Reiner trusted his doctors that this approach was worth the two- or three-week wait to receive the Foundation Medicine report and the specifically targeted treatment, rather than immediately jump into a round of chemotherapy. He is especially grateful now, he says, because the report delivered a great deal of relief from his previously exhausting and growing anxiety about having cancer.
Reiner and his team learned his lung cancer contained the epidermal growth factor receptor (EGFR) mutation. That biomarker enabled his oncologist to prescribe Tagrisso (osimertinib), a medication developed to directly target that genetic mutation.
“Knowing there was a medicine for my particular type of cancer was like a weight lifted off my shoulders,” he says. “It only took a week or two before my cough finally started subsiding. This pill goes right after the particular piece of genetic material in the tumor that’s causing its growth.”
Dr. Jerry Mitchell, director field medical oncology, Foundation Medicine, in Columbus, Ohio, explains that genomic profiling is generating substantial impacts today. “This is a technology that is the standard of care across many advanced malignancies that takes patients from chemotherapy-only options to very targeted options or immunotherapy options,” he says. “You can also look at complex biomarkers, and these are not specific genetic changes but different genes across the tumor to get a biomarker.”
According to Dr. Mitchell, Foundation Medicine’s technology can test more than 324 different cancer-related genes in a single test. Thus, a growing number of patients are benefitting from comprehensive genetic profiling, due to the rapidly growing number of targeted therapies. While not all of the cancers are treatable yet, the company uses that information to partner with researchers to find new potential therapies for patient groups that may have rare mutations.
Since his tumor’s diagnosis, Reiner has undergone chemotherapy and a couple surgeries to treat the metastatic cancer in other parts of his body, but the drug Tagrisso has significantly reduced his lung tumor. Now, having learned so much during the past couple of years, he is grateful for precision oncology. He still reflects on the probability that, had the Tagrisso pill not been available in May 2019, he might have only survived for another six months or a year.
“Comprehensive Genomic Profiling is not some future state, but in both the U.S. and Europe, it is a very standard, accepted, and recommended first step to knowing how to treat your cancer,” says Dr. Mitchell, adding that he feels fortunate to be an oncologist in this era. “However, we know there are still people not getting this recommended testing, so we still have opportunities to find many more patients and impact them by knowing the molecular profile of their cancer.”
As gene therapies and small molecule drugs are being studied in clinical trials, companies increasingly see the value in hiring patients to help explain the potential benefits.
Biomedical corporations and government research agencies are now incorporating patient advocacy more than ever, says Alice Lara, president and CEO of the Sudden Arrhythmia Death Syndromes Foundation in Salt Lake City, Utah. These organizations have seen the effectiveness of including patient voices to communicate and exemplify the benefits that key academic research institutions have shown in their medical studies.
“From our side of the aisle,” Lara says, “what we know as patient advocacy organizations is that educated patients do a lot better. They have a better course in their therapy and their condition, and understanding the genetics is important because all of our conditions are genetic.”
Founded in 2016, Tenaya is advancing gene therapies and small molecule drugs in clinical trials for both prevalent and rare forms of heart disease, says Ali, the CEO.
The firm's first small molecule, now in a Phase 1 clinical trial, is intended to treat heart failure with preserved ejection fraction, where the amount of blood pumped by the heart is reduced due to the heart chambers becoming weak or stiff. The condition accounts for half or more of all heart failure in the U.S., according to Ali, and is growing quickly because it's closely associated with diabetes. It’s also linked with metabolic syndrome, or a cluster of conditions including high blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol levels.
“We have a novel molecule that is first in class and, to our knowledge, best in class to tackle that, so we’re very excited about the clinical trial,” Ali says.
The first phase of the trial is being performed with healthy participants, rather than people with the disease, to establish safety and tolerability. The researchers can also look for the drug in blood samples, which could tell them whether it's reaching its target. Ali estimates that, if the company can establish safety and that it engages the right parts of the body, it will likely begin dosing patients with the disease in 2024.
Tenaya’s therapy delivers a healthy copy of the gene so that it makes a copy of the protein missing from the patients' hearts because of their mutation. The study will start with adult patients, then pivot potentially to children and even newborns, Ali says, “where there is an even greater unmet need because the disease progresses so fast that they have no options.”
Although this work still has a long way to go, Ali is excited about the potential because the gene therapy achieved positive results in the preclinical mouse trial. This animal trial demonstrated that the treatment reduced enlarged hearts, reversed electrophysiological abnormalities, and improved the functioning of the heart by increasing the ejection fraction after the single-dose of gene therapy. That measurement remained stable to the end of the animals’ lives, roughly 18 months, Ali says.
He’s also energized by the fact that heart disease has “taken a page out of the oncology playbook” by leveraging genetic research to develop more precise and targeted drugs and gene therapies.
“Now we are talking about a potential cure of a disease for which there was no cure and using a very novel concept,” says Melind Desai of the Cleveland Clinic.
Tenaya’s second program focuses on developing a gene therapy to mitigate the leading cause of hypertrophic cardiomyopathy through a specific gene called MYPBC3. The disease affects approximately 600,000 patients in the U.S. This particular genetic form, Ali explains, affects about 115,000 in the U.S. alone, so it is considered a rare disease.
“There are infants who are dying within the first weeks to months of life as a result of this mutation,” he says. “There are also adults who start having symptoms in their 20s, 30s and 40s with early morbidity and mortality.” Tenaya plans to apply before the end of this year to get the FDA’s approval to administer an investigational drug for this disease humans. If approved, the company will begin to dose patients in 2023.
“We now understand the genetics of the heart much better,” he says. “We now understand the leading genetic causes of hypertrophic myopathy, dilated cardiomyopathy and others, so that gives us the ability to take these large populations and stratify them rationally into subpopulations.”
Melind Desai, MD, who directs Cleveland Clinic’s Hypertrophic Cardiomyopathy Center, says that the goal of Tenaya’s second clinical study is to help improve the basic cardiac structure in patients with hypertrophic cardiomyopathy related to the MYPBC3 mutation.
“Now we are talking about a potential cure of a disease for which there was no cure and using a very novel concept,” he says. “So this is an exciting new frontier of therapeutic investigation for MYPBC3 gene-positive patients with a chance for a cure.
Neither of Tenaya’s two therapies address the gene mutation that has affected Borsari and her family. But Ali sees opportunity down the road to develop a gene therapy for her particular gene mutation, since it is the second leading cause of cardiomyopathy. Treating the MYH7 gene is especially challenging because it requires gene editing or silencing, instead of just replacing the gene.
Wendy Borsari was diagnosed at age 24 with a commonly inherited heart disease. She joined Tenaya as a patient advocate in 2021.
Wendy Borsari
“If you add a healthy gene it will produce healthy copies,” Ali explains, “but it won’t stop the bad effects of the mutant protein the gene produces. You can only do that by silencing the gene or editing it out, which is a different, more complicated approach.”
Euan Ashley, professor of medicine and genetics at Stanford University and founding director of its Center for Inherited Cardiovascular Disease, is confident that we will see genetic therapies for heart disease within the next decade.
“We are at this really exciting moment in time where we have diseases that have been under-recognized and undervalued now being attacked by multiple companies with really modern tools,” says Ashley, author of The Genome Odyssey. “Gene therapies are unusual in the sense that they can reverse the cause of the disease, so we have the enticing possibility of actually reversing or maybe even curing these diseases.”
Although no one is doing extensive research into a gene therapy for her particular mutation yet, Borsari remains hopeful, knowing that companies such as Tenaya are moving in that direction.
“I know that’s now on the horizon,” she says. “It’s not just some pipe dream, but will happen hopefully in my lifetime or my kids’ lifetime to help them.”