In Part I, we recounted how former oil executive Bonnie J. Addario survived lung cancer and embraced a new calling: patient activism. She started the Bonnie J. Addario Lung Cancer Foundation (ALCF) with two goals: 1) to raise public awareness about the relative neglect of lung cancer in biomedical research, and 2) to help lung cancer patients navigate effectively through the healthcare system toward the best available care.
Addario soon realized the necessity of a third goal: to enlist the aid of physicians and biomedical scientists in the reorganization of cancer research. In November 2007, she convened the first annual ALCF Lung Cancer Summit in San Francisco, and posed a simple question to an audience of prominent oncologists: “If money were no object, what would you do to increase lung cancer survival rates?”
buy Lyrica india Tissue is the issue
Dr. Harvey Pass, Director of the NYU Division of Thoracic Oncology, stood to respond: “We need a bio-repository operated by an honest broker, and collaborative agreements to ensure that institutions donate tissues.” The fight against cancer in the emerging era of genomics and personalized medicine depends crucially on the identification of tumor biomarkers – mutated genes or molecules associated with the development of specific types of malignancies. Biopsied tissues are basic raw materials that researchers need to develop improved diagnostic tests and targeted therapies. As Bonnie puts it, sample collection is “a search for gold.”
The value of biomarkers in the development of diagnostic tests and therapies has been amply demonstrated. In the case of lung cancer, for example, a genetic test is now available to detect a specific mutation in the gene that codes for a protein called epidermal growth factor receptor (EGFR). The mutation causes overexpression of the protein, which leads to aggressive forms of lung cancer (and colorectal, ovarian, and pancreatic cancers as well), tumors that readily metastasize and are resistant to standard chemotherapies. For lung cancer patients who carry the mutation, the best available drug is Genentech’s Tarceva®. Tarceva targets EGFR and inhibits its biological action.
“Think about it this way,” says Bonnie. “A carpenter would never leave the house without a full toolbox – a hammer, a screwdriver, a saw, and so on. Molecular analysis of tissues is the tool that oncologists need to select the right treatment for the unique patients sitting in front of them.”
Oncologists have long collected and analyzed tissue samples in order to characterize, predict, and monitor the progression of tumors. It was never common, however, to share samples broadly. With limited tools and techniques for the investigation of cancer genetics and scarce understanding of the heterogeneity of cancer as disease category, demand was limited. Specimens were regularly discarded after testing. Now, however, genomics technologies permit far greater differentiation in tumor typing. Demand for specimens is growing. Comprehensive identification of mutations and gene expression patterns implicated in oncogenesis will require genomic analysis of large sets of tissue samples.
Resources Boom and bust
In the early 1990s, there were great expectations among genome scientists, entrepreneurs, investors, and drug companies that the identification of genetic markers would streamline drug discovery and development and form the basis of a new sector of the pharmaceutical industry. A large cohort of companies appeared, ready to implement genomics technologies in drug target screening, identification, and validation, but the data licensing business model adopted by most firms proved unsustainable.
Information alone doesn’t make a drug. Drug design involves making safe and effective interventions in strictly regulated and finely tuned biochemical signaling pathways nested in highly complex biological systems. A lot can go wrong. Even if a pharmaceutical company possesses a promising target, there is no guarantee that it will be able to develop an efficacious drug. Most attempts fail. If all goes well in the laboratory and clinical testing – a very rare course of events – then one might expect a drug in perhaps ten years at a cost of half a billion dollars.
Given the length, expense, and uncertainty of the drug development process, pharmaceutical companies questioned the value of biomarkers. What is a fair price? Eventually, the answer became clear: not enough in many cases to support the commercialization of biomarkers as a main line of business. After pharmaceutical houses had made a first pass and selected priority drug development targets, demand for biomarkers slackened. Firms licensing gene sequences struggled to remain profitable. Many genomics companies elected to divert resources to the downstream development of diagnostic products or drugs. Oncologists had anticipated an avalanche of cancer biomarker data, but only a trickle arrived.
Academic labs carried on the study of cancer genomics, but with fewer resources, and in a mostly uncoordinated manner. The advent of genomics has increased demand for tissue specimens by several orders of magnitude, yet competition in science has continued to put pressure on academic laboratories to generate data and publications independently rather than cooperatively. There have been few concerted efforts to pool genomics data in cancer research. There is no central repository.
When Bonnie Addario surveyed the institutional landscape, she saw a case market failure. She was enthusiastic about the promise of genomics for the development of individualized treatments and improved outcomes for lung cancer patients, but frustrated by the organizational and economic impediments to translation of biomedical advances from ‘bench to bedside.’ Attendees at the ALCF Lung Cancer Summit agreed that patients would benefit from changes in the way cancer biomarker data are generated and disseminated.
buy Lyrica online overnight Storming the silos
After the meeting, Bonnie assembled a team to organize the proposed clearinghouse. Joining her as president of the Addario Lung Cancer Medical Institute (ALCMI – pronounced ‘alchemy’) were Steven Young, former Executive Director of the Multiple Myeloma Research Consortium, and a core group of leading oncologists, thoracic surgeons, and laboratory scientists – Harvey Pass from NYU Langone Medical Center, David Carbone of the Vanderbilt University Medical Center, David Gandara, from University of California-Davis School of Medicine, David Jablons, from the University of California, San Francisco, Pasi Jänne from Harvard Medical School and the Dana Farber Cancer Institute, Ite Laird-Offringa of the University of Southern California, Rafael Rosell from the Catalan Institute of Oncology in Spain and Giorgio Scagliotti from the University of Torino.
“These were really the top guys in the business,” says Young, who was appointed President of the organization. As the only non-scientist on the board, Bonnie represented the patient perspective. “I insisted that she have veto power,” says Young, “to make sure that our mission wasn’t hijacked.” Addario was gearing up to wage “a battle against the status quo.” She had selected a board that she believed was willing to reform established institutional processes in biomedical research.
The group formulated goals, established ground rules, and developed a unique operational model. ALCMI was established to break down barriers. Bonnie intended the group to serve as a virtual mediator that would 1) establish connections and facilitate communication between ‘research silos’ (academic and industrial laboratories reluctant to collaborate and share information); 2) link and standardize existing biobanks in a cooperative network; and 3) provide an information technology infrastructure for the broad and efficient dispersion of data across the institutional topography of the global cancer research establishment.
The initial goal, agreed upon at the first meeting of the ALCMI board, was to affect the clinical management of lung cancer in a significant way within three years. The timetable was ambitious. It reflected Bonnie’s “no-nonsense” business approach to leading the consortium. The cancer survivor and former oil company executive had little patience with the established conventions of academic life. “A lot of people were doing good things in cancer research,” she says, “but didn’t fully understand the need to shake up the academic system. We’re running ALCMI as a business. We don’t sit around and create ideas and not implement them. We make sure they happen and we measure what we’re doing. We operate using business principles.”
Fourteen academic universities and community hospitals have joined formally as collaborators. In the United States, participating institutions include the Dana Farber Cancer Institute in Boston, the Hoag Memorial Hospital Presbyterian in Newport Beach, California, the Lahey Clinic in Burlington, Massachusetts, New York University, the University of California, Davis, the University of California, San Francisco, the University of Southern California in Los Angeles, Alta Bates Summit Medical Center in Oakland, Palo Alto Medical Foundation in Palo Alto, Vanderbilt University in Nashville, Tennessee, and Memorial Cancer Institute in Hollywood, Florida. Abroad, ALCMI enrolled programs at the Catalan Institute of Oncology in Barcelona, Spain, the Institut Gustave Roussy in Villejuif, France, and the University of Torino in Turin, Italy. Four additional medical centers in the U.S. have been invited to join ALCMI, bringing the total number of community hospitals to eight— ALCMI is unique in engaging community-based clinicians and community hospitals in translational research.
Despite the urgency of her mission, Bonnie understood that laboratory research moves forward according to its own timetable. Advancing basic science takes time, money, and luck. Breakthroughs can’t be predicted. They can’t be planned. Bonnie believed, however, that promising findings too often circulate for extended periods through restricted academic channels in which interests in publication and tenure take precedence over the translation of research to medical applications. Bonnie and company planned to operate differently. Steven Young says, “ALCMI is not a private playground for scientists in the consortium. We stated that clearly to our academic partners. We said, ‘We’re not trying to continue what you normally do. We’re creating this resource so that scientists around the world can access it.’”
As new member organizations joined and coordination challenges arose, ALCMI evolved into a contractual consortium. In order to gain access to the organization’s bio-repository resources, participating institutions must agree to adhere to non-negotiable policies on control of data and intellectual properties, tissue collection and usage, and revenue sharing. These contractual agreements obviate the need to negotiate separate deals with multiple technology transfer offices. They streamline the process of involving new institutional participants and contributors. The goal is effective collaboration with far less red tape. Through the contract system, ALCMI has been able to re-route flows of information in academic collaborations – investigators and research institutions have evidently recognized the sense and value in ALCMI’s innovative methods.
ALCMI is not the only non-profit organization working to share tissue samples and disseminate biomarker data, but similar groups are few in number. According to Steven Young, “there are only three or four of these around the world. It takes a lot of nerve and a lot of money.” ALCMI is currently the only group dedicated exclusively to the acceleration of lung cancer research.
isotretinoin generic no prescription Remove the bricks, remove the mortar, disseminate the research
Two years ago, ALCMI expanded its bold experiment to include the analysis of tissue and plasma samples. The organization initiated the CASTLE Network Study (Collaborative Advanced Stage Tissue Lung Cancer Network), a networked research project that performs laboratory testing on tumor specimens donated by lung cancer patients. The structure is simple. Late-stage cancer patients provide tissue and blood samples at one of seven participating institutions nationwide. Clinicians perform molecular tests to identify biomarkers that might provide clues about the future behavior of the cancer. The samples remain in the bio-repository as a resource for researchers worldwide; test results are sent to the patient’s doctor to help determine the best course of treatment.
The CASTLE study is the beginning of a move toward improved, personalized treatment plans for lung cancer patients. Participating physician and ALCMI board member David Carbone explains that information provided by the institute “enables physicians to make informed decisions on best available treatments – it often allows them to make earlier therapeutic interventions and to prescribe highly effective, targeted drugs rather than nonspecific and toxic chemotherapies.” CASTLE study findings also help researchers identify new biomarkers and learn more about the genetic preconditions, cascading biochemical pathways, and cellular dysfunctions that characterize cancers in lung tissues.
Research is moving ahead. In April 2011, Biodesix, a molecular diagnostics company located in Broomfield, Colorado, a Denver suburb, began testing tissue samples collected from late-stage cancer patients enrolled in the CASTLE study with a serum proteomics test called VeriStrat®. In January 2012, researchers at the University of California, San Francisco (UCSF), with support provided by the ALCF, developed a similar molecular test in hopes of accurately predicting the future behavior of lung tumors.
Parallel drug testing projects are underway with support from the ALCF. In 2010, Dr. David Gandara, a member of ALCMI’s Scientific Board, and a special advisor for experimental therapeutics at the University of California, Davis (UCD) Cancer Center, began collaborating with Jackson Laboratory-West and the National Cancer Institute Center for Advanced Preclinical Research to test the effects of varied drug regimens against specific tumors. Malignant cells from lung cancer patients receiving treatment at UCD have been engrafted onto multiple mouse models and tested serially for positive responses to newly-developed anti-cancer therapies. The goal, Gandara says, is to identify the specific lung cancer mutations that are most common, and most treatable: “There are at least 150 different types of lung cancer, so every patient a physician sees is going to be a little different. We need to find, say, the five or six characteristics that are shared by all the cancers – the most common mechanisms. That’s where we should focus treatment.”
The ALCF began funding Gandara’s research in 2010. A recent progress report revealed that mice engrafted with variations of the EGFR mutant tumor model showed virtually complete reductions in tumor size when treated with afatinib, a drug being tested by Boehringer Ingelheim for patients with EGFR mutation positive non-small cell lung cancer (NSCLC), in combination with cetuximab (Erbitux®), a monoclonal antibody marketed by Bristol-Myers Squibb and Eli Lilly and Company that targets EGFR receptors. Clinical trials of the experimental combination therapy in human beings are underway, after the encouraging preliminary results in animal testing.
Developing alternative treatment options also requires enrolling more patients in clinical trials. Pharmaceutical companies often struggle with recruitment. Fewer than 5 percent of lung cancer patients participate in tests of experimental therapies. As a former patient, Bonnie understands their reluctance: “Most people think of clinical trials as a last resort. They think it signals the end of the road.” For many people with cancer, entering a clinical trial marks a passage in status, from patient receiving care to doomed guinea pig. She has firsthand experience with the phenomenon. When her cousin was diagnosed with pancreatic cancer, the doctor recommended a clinical trial. At her cousin’s next appointment, a trial representative walked into the physician’s office wearing a suit and carrying a briefcase full of enrollment paperwork detailing risks. The reaction from Bonnie’s cousin was immediate and powerful: “No way.”
Bonnie is mobilizing the ALCF to develop more effective enrollment techniques: “I tell patients that at one point, Tarceva was in a trial, and that the people who took it lived longer. We can get patients into clinical trials, but we need to educate them. We have to explain what trials are all about, and tell how genomics is enabling the invention of better medicines.” Her message is that clinical trials give patients the best chance for survival. As Steven Young indicates, the ALCF’s patient recruitment effort is an important piece of the virtual network: “ALCF can get access to the patients, ALCMI has access to the scientists, and we have established an infrastructure to support the research. Our contracts, our data systems, our processes for doing correlative science studies are changing lung cancer research and care.”
Lung cancer education
In 2012, the ALCF and ALCMI have launched further initiatives to inform and empower patients and enlist the aid of healthcare professionals. Working collaboratively with GE Healthcare Oncology Solutions, ALCF is developing the Patient 360 program. A pilot version has been introduced at El Camino Hospital in Mountain View, California, under the direction of Dr. Shane Dormady. The ALCF is also compiling a “360 Degree Patient Handbook” for patients, their families, and health care providers. The handbook is a goldmine of information covering all aspects of the lung cancer experience including diagnosis, cancer staging, targeted treatments, and clinical trials. Bonnie recalls her own firsthand introduction to the world of oncology: “Everyone kept saying that cancer is a journey, but no one could provide me with a roadmap. This handbook is the culmination of years of research, conversations with lung cancer experts and patients, and my personal experience.” A free iPhone app will alert patients of new discoveries and breakthroughs in lung cancer research.
Bonnie insists that the best patient advocates are educated patients themselves. The ALCF is working hard to encourage and enable informed, proactive participation by patients and families in cancer care: “We want to teach the patient what to ask for from the very beginning of the long hard road on which they will travel. When the doctor says, ‘You have a metastasis to the brain, you need radiation,’ they will have the background knowledge to reply, ‘Well, are we considering whole brain radiation, gamma knife, or cyber knife procedures?’ They will be able to personalize their treatment and demand a seat at the table.”
Before patients demand a seat at the table, they are offered a space on a couch at the ALCF Lung Cancer Living Room support group. The Living Room is an open forum for patients and their families to voice questions and concerns, share lessons learned, and hear from experts in the field of lung cancer research and medicine. Recently, Living Room conversations debuted on the worldwide web. “We are now live streaming into patient’s homes,” Bonnie reports. “It’s open to anyone who wants to dial in, and that includes the pharmaceutical industry. We are not restricting access. We are not keeping anyone out.”
These patient-focused programs are part of a larger campaign by the ALCF and ALCMI to reshape the institutional foundations of cancer care. Efforts to create more knowledgeable, more responsive, and better equipped community hospitals are another important part of the process. Seventy to eighty percent of all cancer patients are treated at community hospitals, but molecular testing is far from a widespread or standard procedure, and many patients do not learn about the latest treatment options. “Patients are getting the same old, same old,” says Bonnie. “Whatever the oncologist was giving them before, that’s what they’re kept on.” ALCF is spearheading a community hospital referral program. The program is designed to provide community hospitals with incentives to improve, to acquire the tools and forms of expertise required to diagnose and treat cancers based on the results of personalized molecular testing. And if superior resources or specialists are to be found elsewhere, the ALCF will refer patients out to complete their treatment at different hospitals.
“The tissue under the microscope”
Bonnie J. Addario has extended patient activism to the formation of a virtual research network that links cancer patients, oncologists, biomedical researchers, and pharmaceutical companies in order to realize the potential of cancer genomics and personalized medicine. She is attempting to tear down institutional walls and push scientific and medical experts to work smarter and more cooperatively in order to save more lives. Her message to researchers, physicians, and industry leaders is that their work is profoundly important to cancer patients and their friends and families – never forget it! The tissue under the microscope, she reminds them, came from a human being who desires to live: “When you go back to your labs, remember that you’re not just looking at cancer cells. You’re looking at a patient. This person has given you their tissues, their cells, to help you advance lung cancer care.”
“We’re in the phase now,” says Bonnie, “where we have identified a genetic mutation or bio-marker for something like thirty or forty percent of lung cancers. Many of them we can treat.” The mission shared by the ALCF and ALCMI is to identify the other sixty percent and make sure that patients know about it. Bonnie sums up the project: “We partner and collaborate with academic institutions, pharma corporations, and biotech firms. We take our most prized possessions and share them in order to speed the delivery of life-saving medical products to patients. We have to do it.”
Reflecting on her life and luck, Bonnie says, “When I became President of Olympian Oil, someone said to me, ‘You’re really lucky.’ I thought, ‘Me? Lucky?’ But then I realized I was lucky. I loved what I did every day. But I also realized that I hadn’t been called to do it. I didn’t know what I was meant to do, but I knew my job at Olympian wasn’t it. Now I know. This is it. What more can we do, what better footprint can we leave, than to say ‘I saved a life?’ Even if it’s just one, that’s pretty good.”