BIDMC Cancer Center: Exploiting biology to outwit cancer
"Our central vision in the Cancer Center is translating the research of basic scientists into the solution of clinical problems," says Lowell Schnipper, MD, chief of the Division of Hematology/Oncology at Beth Israel Deaconess Medical Center, as well as deputy associate director for Clinical Sciences and member of the Executive Committee at DF/HCC. To fulfill that vision, numerous research programs are driving discovery from the bench to the bedside at this 100-year-old institution. Three areas of excellence, in particular, are exploiting the biology of cancer -- to outwit it.
Pathways to Personalized Medicine
One such effort comes from the laboratory of Lewis Cantley, PhD, chief of the Division of Signal Transduction at BIDMC, as well as deputy associate director of Basic Science and member of the Executive Committee at DF/HCC. More than a decade ago, Cantley’s lab co-discovered the critical enzyme PI3 kinase (PI3K), which subsequently led to the discovery of a new signal transduction pathway. Since then his research has sought to unravel the intricate tangle of all biochemical pathways and to decipher which ones conspire to cause cancer.
As basic scientists like Cantley are discerning which pathways are perturbed in various subtypes of cancer, pharmaceutical companies are rapidly developing dozens of new inhibitors - for PI3K, EGFR, HER2, Ras and other signaling molecules – that target specific mutations in the cancer cell. “The challenge will be to identify the subset of patients likely to respond to each of these new pathway-specific drugs, which will dramatically shorten the cost and time required for clinical trials,” notes Cantley. “The real future of cancer research will be individualized patient treatment.”
What is needed, he says, is a universal, standardized technique for collecting and storing tumor specimens so that pathologists can use immunohistochemical (IHC) staining with antibodies that reveal the activation state of signal transduction pathways. When activated, proteins often become phosphorylated, and antibodies specific to phosphorylated proteins are readily available. “But if the specimen has sat in an ice bucket for an hour, prior to fixation, the phosphates could fall off, thereby compromising the reliability of diagnosis and of microarray analysis of gene expression profiles,” explains Cantley. “The most important effort in translational research at BIDMC is developing better tumor banks and better ways to interrogate tumors so that what we’re learning about the molecular basis for cancer from studies with mouse models can be applied to diagnosing and treating humans.”
Cantley envisions tumor banks that maintain the molecular integrity of their specimens and include software to annotate the tumor with patient information - including consent, outcome, and primary mutations or activation state of pathways. He is now spearheading a fundraising effort to make this possible, using as a blueprint the well-annotated prostate tumor bank developed by Glenn Bubley, MD, director of Genitourinary Medical Oncology at BIDMC. The new tumor bank will be integrated into the DF/HCC Virtual Specimen Locator and shared throughout member institutions.
Reeducating the Immune System
The millions of foot soldiers in the immune system’s army normally mount an attack when they spot a foreign invader. But cancer cells, like stealth missiles, can evade detection and penetrate the body’s defenses. Another research effort at BIDMC, led by David Avigan, MD, director of the Bone Marrow Transplantation and Hematologic Malignancies Program, seeks to thwart this scenario by creating vaccines that expose the invaders and alert T cells to stage an offensive.
These autologous vaccines fuse dendritic cells with cancer cells to reeducate the immune system on what to attack and what to ignore. Dendritic cells are special immune cells that sample their surroundings and trigger a response when encountering pathogens, properties useful for a vaccine. As dendritic cells confront cancer antigens, they split them into small peptides and display them on their surface to alert the rest of the immune system to assist in the assault. Since the fused cells have all the proteins of the patient’s tumor, they can evoke a broad immune response against the multiple antigens presented by the dendritic cell. “And what’s very appealing about this approach is that it holds the potential to induce long-term memory and prevent recurrence of disease,” says Avigan.
Working in collaboration with Donald Kufe, MD, of DFCI, Avigan completed a number of studies in animals and in human tissue, which demonstrated that the vaccine could stimulate an immune response; he then set up an immunotherapy facility at BIDMC in preparation for the leap into clinical trials. In the first study, Avigan’s team harvested tumor and white blood cells from patients with metastatic breast or kidney cancer, grew the dendritic cells in the lab, and then fused them with the patient’s cancer cells, carefully documenting the number of fusions and determining the correct dose. These Phase I trials demonstrated tolerability, feasibility, immune response in a majority of patients, and some evidence of clinical activity.
“Our biggest challenge in cancer vaccines is that we’re dealing with patients with compromised immune systems and advanced disease,” explains Avigan. “So the next step was to see what could be done to overcome that.” In one ongoing trial, the immunotherapy group augmented the vaccine by adding growth factors, including GM-CSF, which help kick-start the immune system. In another, investigators are administering the vaccine immediately following an autologous stem cell transplant to wipe out residual disease in myeloma patients. “There’s some evidence that the high-dose chemotherapy used in transplants may eliminate some of the defenses tumors have set up to evade detection,” notes Avigan. Thus administering the vaccine in the immediate post-transplant period may amplify the reaction of the immune system. Studies in patients with kidney cancer employ a similar strategy, combining surgical removal of the tumor with a GM-CSF-boosted vaccine. In the works are breast cancer trials, in which the immune-activating drug interleukin 12 will be combined with the vaccine, and ovarian cancer trials involving vaccination using viral vectors.
“These vaccine trials are integrated into many of the SPORE grants sponsored by DF/HCC,” comments Schnipper, “and represent an ideal model of research: an investigator at one institution leading clinical trials available to patients across the entire cancer center.”
Exploiting an ‘Achilles Heel’ in Kidney Cancer
According to Michael Atkins, MD, deputy chief of the Division of Hematology/Oncology and director of the Cancer Clinical Trials Office at BIDMC Cancer Center, kidney cancer’s underlying etiology makes it unique. About 50% to 60% of patients with clear cell kidney cancer have mutations in the von Hippel-Lindau tumor suppressor gene, leading to upregulation of hypoxia inducible factor (HIF), which in turn activates vascular endothelial growth factor (VEGF), a key mediator in tumor angiogenesis. This dependence on VEGF – an ‘Achilles Heel’ to be exploited – has opened new therapeutic opportunities in the fight against kidney cancer.
“In the last three years, this discovery, to which DF/HCC scientists contributed, has led to a revolution in treatment of patients with advanced kidney cancer,” says Atkins. Four new antiangiogenic therapies are now being tested: two small-molecule drugs that block the receptor for VEGF on blood vessel cells (sorafenib and sunitinib), a monoclonal antibody that binds VEGF directly (bevacizumab), and an agent that decreases HIF by inhibiting the molecule mTOR (temsirolimus).
As leader of the DF/HCC Renal Cancer Program and principal investigator of the Renal SPORE - the only SPORE awarded by the NCI for the study of kidney cancer - Atkins is driving the academic effort to answer some key questions:
- What’s the best combination of these agents for optimal synergistic effect?
- What’s the mechanism of resistance to these agents (because tumors do progress over time)?
- Which patients should receive which therapies?
For answers, Atkins and colleagues are conducting a series of preclinical studies, as well as PhaseI/II clinical trials evaluating the combination of sorafenib and bevacizumab and the combination of sunitinib and temsirolimus. “Our hope is that in the next 3 to 5 years we’ll be able to clearly define who should get which agent first, which combinations are optimal, and what the treatment approach should be for those patients who become refractory to these agents.”
“Tackling a problem like kidney cancer is so huge,” says Schnipper, “that you can’t do it within the confines of one institution. “I think the best thing that DF/HCC has done is to catalyze the concept that we’re all in the same boat, pulling with the same oars. It creates the opportunity to do big science.”
Image above: Specimen of bone tumor from patient with metastasized prostate cancer. Brown stain reveals antibody recognition of phosphorylated AKT, indicating activation of the PI3K pathway. [from the prostate tumor bank of Glenn Bubley, MD, BIDMC]