“In the old days we treated everyone with prostate cancer with the same drugs, and you never really knew whether the treatment worked — or why it didn't. We now realize that cancers with very similar outward symptoms can be driven by genes A, B or C. So, if we have a drug for gene A, we don't use it needlessly to treat people with gene B or C.”
Two events accelerated the ascendance of what we now call molecular medicine in oncology and every other field. The first was the announcement in 2001 of a “rough draft” DNA sequence of all 23,000 or so genes in the human genome, providing scientists with an “everyman” prototype of what that sequence ought to look like in a healthy (and yes, white and male) human being. That event was followed by the invention a few years later of next-generation DNA sequencing machines capable of sequencing any person’s genome (or even a dog’s) rapidly and, most important, cheaply.
Rapid sequencing technology, coupled with availability of computer-based data analysis tools, ushered in a post-genomic age in which it was suddenly feasible to sequence any patient’s DNA, as was prescribed in 2012 for the teenager with AAA syndrome. In her case, physicians found an error in a stretch of DNA, or gene, that tells cells how to build a very common nuclear protein called Aladin. That single error in the 3 billion repeating units that make up the young girl’s genome was sufficient to botch Aladin construction and inflict her with symptoms so mystifying that only genomic analysis could nail down the cause. Ten years earlier, that diagnosis might not have happened.
These same technologies have in the last decade hastened progress on numerous fronts. Metastatic melanoma in 2016 is simply not what it was in 2001. Monolithic treatments for autism or heart disease seem equally unthinkable. The idea that a patient’s DNA sequence should inform treatment is now so commonplace that in his 2015 State of the Union address, then-President Obama launched a Precision Medicine Initiative by forecasting cancer cures based on a patient's tumor genetics.
Genetic approaches have thus moved from the lab to the clinic, where they are having a tremendous impact in almost every realm of biomedicine. But small wonder the president chose cancer as the exemplar in his speech: In few arenas have precision approaches advanced as far and as fast as in oncology, in which genomics is a now major focus of basic and clinical research.
Prostate cancer: to treat or not to treat
There is nothing new about precision diagnostics: Anyone who has had a Pap smear or a PSA test has at least been assigned to a group with quantifiable disease risk to help his or her doctor decide on appropriate treatment. What is new is just how molecularly precise diagnoses and treatments have become. In the past, cancer suspicions were confirmed primarily by abnormal appearance of cells (as in the Pap smear), the presence of unusual proteins in the bloodstream (as in the PSA test) or inexplicable opacities in a chest X-ray. Now there’s a brand-new tool in the toolbox, one that's getting a lot of use: the sequence of a patient’s tumor DNA.
Cancer doctors at UCLA routinely order sequencing of a patient’s tumor DNA for around $1,000 and can have the results (either the sequence of all of a patient's genes or of a subset of 200 or so cancer-related genes) in a couple of weeks to begin the search for mutations, or errors, in the sequence of suspect genes. Once they find them, many serve as diagnostics to predict how aggressively a tumor may be growing.
Robert Reiter is a urologist, prostate cancer specialist and principal investigator of UCLA’s SPORE (Specialized Program in Research Excellence) program in prostate cancer; he also directs the prostate cancer program at the Geffen School of Medicine. He says molecular diagnostics have helped answer a vexing question unique to prostate cancer: whether to treat it or leave it alone, as some prostate tumors are extremely slow-growing. Historically, he says, that decision was based primarily on either assigning a Gleason score (which rates how abnormal one’s prostate cells look under a microscope), or blood levels of the PSA biomarker, or a patient’s age or tumor size.
“Physicians would recommend surgery and radiation for aggressive tumors, but the problem was knowing whether that was warranted,” Reiter said. “Now we have a commercially available molecular test that measures expression of 17 different genes that constitute what is called a prostate cancer signature. Depending on their expression, tumors are scored as indolent or aggressive.” These tests have by no means replaced PSA or Gleason scores or even novel imaging techniques, which Reiter himself has developed, as prostate cancer diagnostics, but they have become one more important data point.
As are all oncologists, Reiter is interested in looking for so-called oncogenic mutations that don't simply mark cancer but actually cause it, in hopes of applying or designing drug treatments to block them. In that effort, he is researching pathway-specific treatments for patients with the most deadly form of prostate cancer, metastatic drug-resistant prostate tumors. As a participant in Stand Up to Cancer's multi-institutional West Coast Dream Team, co-led by his UCLA colleague Dr. Owen Witte, his goal is to define those A, B or C genes enabling metastatic prostate tumor cells to survive and keep dividing after patients stop responding to anti-androgen therapy. Knowing that could suggest individualized interventions to target each pathway.
A prototype of precision oncology: melanoma
UCLA physician/scientist Dr. Antoni Ribas received one of 12 “Giants of Cancer Care” awards given in 2015 to individuals achieving monumental success in oncology. Ribas’ work is in melanoma research. Accepting his award, Ribas recalled being a young oncologist in Barcelona and leaving his home for UCLA 20 years ago “because I wanted to do something different than just administer chemo all my life.”
His was an informed choice: By then, the stage had been set in Westwood for two of the first targeted anti-cancer therapies (i.e. the first examples of precision medicine treatments for cancer). In the 1980s, UCLA's Dr. Dennis Slamon had discovered that a gene called HER2 was amplified in 25 percent of breast cancers, leading to clinical development of the anti-Her2/neu antibody trastuzumab (Herceptin), a blockbuster drug that targets HER2/neu-positive metastatic breast cancer. Likewise, in 1986, UCLA’s Witte discovered that a mutation causing fusion of the genes BCR and ABL activated a signaling factor called a tyrosine kinase, causing normal white blood cells to become leukemic. That work led to development a drug called imatinib (Gleevec), which in 2001 was approved by the FDA to treat chronic myelogenous leukemia.
At UCLA, Ribas trained with surgeon and renowned tumor immunologist Dr. James Economou a pioneer of cancer immunotherapy. Back then, however, melanoma prognoses were dismal, and Ribas says colleagues questioned why he was wasting time working on something as far-fetched as immunotherapy.
“At the time someone said that melanoma is the cancer that gives the field of medical oncology a bad name,” said Ribas, who now directs the Tumor Immunology Program at UCLA’s Jonsson Comprehensive Cancer Center. “In the clinic, the only available treatment worked in maybe one in 20 people, and by treatment I mean palliation.” Those numbers have changed drastically in the last five years. “One-third of my patients lead a normal life because precision treatment strategies based on science are now applied to patient care. We aren't treating patients by trial and error anymore.”
Ribas has made enormous contributions to the fields targeted therapies for melanoma and immunotherapies, the first a textbook example of precision genomics. Oncologists have long known that about 40 percent of patients with melanoma harbor a mutation in an oncogene called BRAF, which drives their cancer. A front-page cancer news story five years ago reported on the development of so-called targeted BRAF inhibitors, drugs that — like Herceptin in breast cancer or imatinib in leukemia — muffle an overactive oncogene.
The first BRAF inhibitors worked miraculously, achieving a positive response rate of close to 80 percent in clinical trials, some conducted at UCLA under Ribas’ supervision. But effects were short-lived: Patients rapidly relapsed as tumor cells adapted and learned to resist the drug. Then in 2011, Ribas and UCLA dermatologist Dr. Roger Lo implemented a clinical trial pairing BRAF inhibitors with a different class of drugs that block cell division called MEK inhibitors, a so-called combination therapy. That trial changed treatment paradigms for melanoma patients, producing a much more durable anti-tumor response and prompting the FDA to approve the anti-BRAF/anti-MEK combo by the end of 2015. That drug pair is now standard care for the subset of patients who harbor BRAF mutations.
The immunological investigations Ribas began two decades ago are beginning to reap huge rewards: Immunotherapies, defined as strategies to activate a patient's own immune system to target a tumor, have achieved breakthrough status as melanoma therapies. “There is no better precision medicine than having your own immune system attack a cancer. Anything else is second best,” Ribas said. “We estimate that in one-third of our patients, immune t cells stand ready to attack a cancer, but the receptors they use to ‘see’ a tumor are nonfunctional. By making itself invisible to t cells, the cancer has found way of protecting itself.”
Immunologists know that the way t cells become “blind” to cancer is through a protein called PD-1, which blocks or fogs those tumor-recognizing receptors on immune cells, thwarting an attack. To test a class of drugs developed to neutralize PD-1 as anti-tumor reagents, Ribas served as principal investigator on pivotal investigations of the PD-1 inhibitor pembrolizumab (commercialized as Keytruda). Those trials led the FDA to designate the drug a breakthrough therapy and approve it for use in 2014.
The success of melanoma immunotherapies made headlines when former President Jimmy Carter made the astounding announcement that he is free from metastatic melanoma to the liver and brain after pembrolizumab treatment. But the precision caveat is that PD-1 inhibitors are not one-size-fits-all drugs; only some patients respond to them. Why some don’t is now an area of active investigation. Ribas recently published work in the prestigious journal Nature proving that it is at least possible to predict positive responders based on conventional biomarkers and DNA sequencing. “Our concern now becomes what we can do for the subset of patients unlikely to respond,” he said.
Targeted cancer treatment: “The right drugs for the right patients”
UCLA oncologist Dr. Dennis Slamon, whose research led to the development of Herceptin to treat some breast cancers, thinks oncology is one of precision medicine’s great success stories. But among cancers, he calls breast cancer the paradigm setter. “Breast cancer has revealed that what we thought was one disease actually has diverse origins and outcomes,” he said. “The development of effective therapies to treat molecular subtypes of breast cancer has led the way.”
Slamon speaks with authority on the topic: He has played multiple roles in initiating breakthrough treatments for two breast cancer subtypes (and for the first was portrayed by Harry Connick Jr. in a Lifetime movie). As his colleague Ribas said, “Dennis is a person who changed the cancer world twice.”
The first came in the early 1980 when Slamon’s research, described previously, led to the development of Herceptin to treat some breast cancers using the gene encoding a protein called HER2.
The second came in 2009, when Slamon and UCLA medical oncologist Dr. Richard Finn reported tests showing that a drug that blocks cell division slows the growth of some human breast cancer lines. Investigators already knew that drug blocked activity of cell division proteins called cdk4/cdk6, but Slamon’s and Finn’s work proved it was particularly potent in halting cdk4/cdk6 in cancers positive for a hormone receptor called the estrogen receptor (ER). This was a therapeutic breakthrough: Until then, ER+ breast cancers, particularly those lacking targetable HER2 proteins, were treated with either traditional, untargeted chemotherapies often associated with nausea and fatigue or with drugs that lowered estrogen levels, such as tamoxifen or letrozole.
Slamon’s and Finn’s work launched clinical testing of the anti-cdk4/cdk6 drug in a phase I/II study combining it with letrozole in patients considered particularly challenging to treat, namely those with advanced metastatic ER+ breast tumors. That trial reported significantly higher progression-free survival for patients treated with the drug combination than those receiving letrozole alone. By 2015, after completion of a phase III study led by Finn, the FDA granted the drug “breakthrough therapy” status, allowing it to be fast-tracked for approval.
It is now marketed as the drug palbociclib (or Ibrance) and recommended as therapy for the subset of tumors known as ER+ or “luminal” breast tumors. In this case, what Finn calls “getting the right drug to the right person” occurred at an unusually rapid pace.
Nonetheless, hormone receptor-negative breast cancers are relatively resistant to palbociclib, leaving patients with so-called triple negative tumors — meaning they do not show aberrantly upregulated hormone or HER2 receptors — still in need of treatment options that go beyond chemotherapy.
“We have no targeted therapy for these cancers yet,” Finn said. “But now we know that what has been called ‘triple-negative cancer’ is itself not one disease; there are subgroups within it.” Finn says that among the latter, mutations now in the crosshairs of drug development include the BRCA 1/2 oncogenes.
Slamon agrees that treatment for triple-negative cancers remains the field’s greatest unmet need, but he is hardly resting on past successes in any area. “There are patients who respond to targeted therapies and some that don’t, so there is still plenty of work to do in all breast cancer subtypes,” he said. “At UCLA we are always searching for better approaches.”