Fifth Annual BIDMC Cancer Symposium ― Gastrointestinal Cancer ~ New Frontiers
Ten years ago, getting diagnosed with lung cancer was nearly always recognized as a death sentence. That’s no longer the case thanks to researchers who have developed targeted drug therapies to attack the disease at the molecular level.
“It’s amazing that we now have clinical trials of targeted therapies for 50 percent of non-small cell lung cancer,” said Lewis Cantley, PhD, Director of the Cancer Center at BIDMC, who with Pier Paolo Pandolfi, MD, PhD, Director of Research at the Cancer Center, moderated the fourth annual BIDMC Cancer Symposium Nov. 30.
The Joseph B. Martin Conference Center at Harvard Medical School was filled to capacity throughout the daylong conference as fourteen leading researchers spoke to theme of “Lung Cancer: Molecular Genetics and Targeted Therapies.”
Though targeted therapies work for some forms of lung cancer, the disease is still the most lethal of all types of cancer. Approximately 150,000 Americans die of lung cancer each year, according to the Centers for Disease Control and Prevention. Worldwide, the disease claims a million lives annually.
Despite the statistics, “there has never been a better time to be coming into this field,” speaker Thomas Lynch, MD, Director of the Yale Cancer Center, told the audience, which included not only scientists and physicians, but also many graduate students. “Progress is moving remarkably fast.”
An Era of Targeted Therapy
A decade ago, “lung cancer was a depressing disease. Most people died within one year,” said Daniel Costa, MD, PhD, MMSc, Thoracic Oncology at BIDMC. “People thought lung cancer was one disease, so they treated it as one disease.”
By 2004, however, three scientific teams, all led by Symposium speakers, discovered that approximately 15 percent of non-small cell forms of lung cancer harbor mutations in EGFR, a growth factor receptor, and that the drugs gefitinib (Iressa) and erlotinib (Tarceva) inhibit the action of EGFR in these lung cancers.
For patients whose tumors have EGFR mutations, these drugs, also called tyrosine kinase inhibitors, are more effective than chemotherapy and they have fewer side effects. In fact, said Lynch, the original patient that led them to this discovery is still alive and still taking the same EGFR inhibitor.
Such long term success on the drug, however, is unusual. By 2005, speaker Susumu Kobayashi, MD, PhD, Hematology/Oncology at BIDMC, had reported in work done in Daniel Tenen’s lab at BIDMC, that patients on gefitinib with relapsing lung cancer develop resistance to these drugs. In biopsies of these recurring tumors his group identified a new EGFR mutation, T790M, that blocks the drug.
Today, said Costa, researchers are looking deeper into the mutations seen in EGFR in lung cancer patients to better guide treatment. Not all EGFR mutations are alike. Indeed, other speakers reported that patients with tumors that have a specific type of EGFR mutation—insertions in exon 20 of the gene—don’t respond well to gefitinib and erlotinib.
At the same time new drugs designed specifically to inhibit mutated EGFR (as opposed to gefitinib and erlotinib, whose EGFR mutation-inhibiting actions were discovered after the fact) are beginning to emerge. “We are seeing people becoming specialists in each type of mutation.” said Costa. “So there may someday be a gamut of drugs for each one type.”
For tumors that don’t have EGFR mutations, other targeted drugs are emerging rapidly. Bruce Johnson, MD, Director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Center, discussed the adoption of a drug called crizotinib for patients with ALK rearrangements, movements of fragments of genes from one chromosome to another that alter protein expression levels. The initial translocations were discovered in 2007, an inhibitor was found in 2008, and the FDA approved its use in patients with non-small cell lung cancer with ALK rearrangements this fall.
Beyond Traditional Targeted Therapy
Costa, Kobayashi and others are also beginning to look at downstream targets. For instance, the T790M mutation in EGFR changes the downstream signaling in a way that prevents the activation of another protein, called BIM, that encourages unhealthy cells to die. “So how do we increase BIM activity?” asked Kobayashi. His lab is investigating the use of drugs that inhibit Bcl-2, a BIM inhibitor, to encourage cell death.
Tyler Jacks, PhD, Director of the Koch Institute for Integrative Cancer Research at MIT, is investigating the use of microRNAs, gene silencing nucleic acids, to stop cancer growth. He found that one such microRNA, called mir-34, prevents lung cancer and stops its growth in mice genetically engineered to develop lung cancer. He is now collaborating with engineers at MIT to use nano-scale bubbles to carry the nucleic acids into the lungs. “Tumors don’t melt away, but this is just the beginning,” said Jacks.
“I don’t think tyrosine kinase inhibitors are going to be enough to cure patients,” said speaker Jeffrey Engelman, MD, PhD, Director of Thoracic Oncology at the Massachusetts General Hospital Cancer Center, who found that patients with higher levels of BIM in their lung tumor cells tend to fare better with EGFR inhibiting drugs. “I’m very interested in orthogonal treatments.” That is, it’s time to start thinking outside of the box.
Targeting the Un-targetable
While 14 percent of non-small cell lung cancer patients have EGFR mutations, and 7 percent have ALK mutations, 23 percent have KRAS mutations, a protein widely considered to be non-druggable. That is, it cannot easily be blocked by a small molecule.
For patients with KRAS mutations, Karen Cichowski, PhD, Associate Professor of Medicine at Brigham and Women’s Hospital, presented a novel therapy that exploits the high stress tumor cells are under by going after their stress coping mechanisms. For example, tumor cells accumulate unfolded and misfolded proteins in the endoplasmic reticulum. Normally, such high levels of stress kills the cell, but many cancer cells have hyperactivated HSP90, a protein that cleans up the mess.
A drug called IPI504 deactivates HSP90. “Used alone, it has little effect,” said Cichowski, but when used alongside rapamycin, an mTOR inhibitor in trials for some forms of lung cancer, tumors shrink by nearly half and up to 80 percent. A trial of a combination of IPI504 and everolimus, another mTOR inhibitor, is underway.
Fishing for More
The complexity of categorizing lung cancer and identifying root causes and potential treatments begs for new methods. For instance, The Cancer Genome Atlas (TCGA) project, described by Matthew Meyerson, MD, co-director for Cancer Genome Discovery at Dana-Farber Cancer Center, is using genomic analysis of squamous cell lung cancer tissues to search for new drug targets. One potential new target is DDR2. Though the biology is not yet clear, said Meyerson, lung cancer trials of desatinib, which inhibits DDR2, are beginning.
Co-clinical trials, drug trials that mirror human trials but are done in mouse models of disease, can also help accelerate discovery, said Kwok-Kin Wong, MD, PhD, Associate Professor of Medicine at DFCI. For instance, Wong is using mice that developed resistance in an ALK trial to understand the mechanism of resistance. The trials done so far, said Wong, have “striking synergy” with human trials.
“This is rarefied air,” said Lynch, who in his talk discussed novel immunotherapies and the potential for combination therapies to help prevent the emergence of resistance. “There is a small world of people who are thinking about lung cancer this way.”
Other speakers included Anton Berns, PhD, Director of Research at The Netherlands Cancer Institute; Daniel Haber, MD, PhD, Director of the MGH Cancer Center; Pasi Jänne, MD, PhD, Director of the Translational Research Laboratory at DFCI; Carla Kim, PhD, Principal Investigator of the Stem Cell Program at Children’s Hospital, Boston; and Katerina Politi, PhD, Assistant Professor of Pathology at Yale University School of Medicine.
-- Elizabeth Dougherty , Freelance for BIDMC
