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Crossing the Barrier to Treating Brain Cancers

PI3K mediates the transforming and growth-stimulating potential of common oncogenic tyrosine kinase receptors that contribute to solid tumors. In about 15% of glioblastoma tumors, PI3K pathway activation plays a central role in cancer growth, survival, motility, metabolism, and angiogeneis. Another 45% of glioblastoma tumors lack a functioning tumor supressor, PTEN, which normally can shut down the PI3K pathway. Wen et al, Phase II clinical trial of P13K inhibitor BKM120 for glioblastoma, Neuro-Oncology, 2012, Volume 14(7):819-829, by permission of Oxford University Press.

Brain tumors are among the most dreaded of cancers, and they were among the first cancers that the National Institutes of Health (NIH) selected for “genomic profiling” – an exercise that reveals genetic or molecular alterations that promote or drive the cancer. Even so, brain cancer patients have yet to benefit from targeted therapeutics (“smart drugs”) designed to selectively kill tumor cells in the patient while sparing normal cells.

Several factors contribute to the challenge facing neuro-oncology, aside from the inherent complexity of the brain. Many brain cancers are fast growing and fatal, and tumors may occur in inoperable or diffuse areas. Any surgery on the brain is risky, and repeat biopsies are out of the question unless a second surgery is otherwise required, such as if a discrete tumor mass recurred in an accessible area. Moreover, many anti-cancer therapeutics do not penetrate the brain, which has a natural defense, called the blood-brain barrier, that protects it from toxins circulating in the body. This difficulty has limited the ability to test targeted therapies in brain cancer patients, but now several new agents cross this barrier.

DF/HCC is currently testing, or will soon be testing, the first agents that target genetic aberrations that distinguish several major classes of brain tumors. One of these therapeutics homes in on PI3K and another on EGFR, both important targets in many cancers and also in glioblastoma, or grade 4 (most aggressive) glioma. This is the cancer that killed Senator Edward Kennedy, and about 10,000 people receive a diagnosis of glioblastoma each year in the U.S. Patrick Wen, MD (DFCI) and Tracy Batchelor, MD (MGH) are leading these trials, respectively.

The groundwork for this and other clinical research was laid down, often years ago, in basic research at DF/HCC, says Charles Stiles, PhD (DFCI), who with Robert Martuza, MD (MGH), directs the Program in Neuro-Oncology at DF/HCC. “We promote a bench-to-bedside approach, taking fundamental discoveries through translational work and clinical trials that lead to new therapies for patients.” This process starts with basic research to define the targets and discover how to attack them, followed by genetically profiling patient tumors to see which molecular anomalies they carry, and then meticulous pre-clinical work with new drug compounds. The final steps involve clinical studies of the compounds in the appropriate population of patients, and validating that the drugs themselves are working as intended and are responsible for the benefits in terms of tumor response, progression-free survival, or prolonged survival.

Tackling Glioblastoma From Discovery Through Therapy

A good example of the bench to bedside approach, says Stiles, is DF/HCC’s work in glioblastoma. Glioblastoma tumors are fast growing and invasive. The standard of care calls for surgery if possible, followed by treatment with the chemotherapeutic temozolomide (Temador) and radiation. But because tumors invade diffusely into neighboring brain tissue, the cancer cannot be completely excised through surgery. Moreover, the tumors are resistant to chemotherapy and radiation. As a result, newly diagnosed patients have a median survival rate 15 months and 5-year survival rate of just 10 percent. Neuro-oncologists urgently want to offer their patients more effective treatments.

Introducing new glioblastoma treatments was not the immediate agenda of biochemist Lewis Cantley, PhD (BIDMC), when he began studying cellular metabolism in the 1960s. He wanted to decipher the signaling pathways that control cell growth and division, with a special interest in cancer. In the 1980s, he and Thomas Roberts, PhD (DFCI), discovered a signaling molecule, phosphatidylinositol 3-kinase (PI3K), and showed that it coordinates growth signals with the availability of nutrients via a molecular relay in the PI3K pathway. Over the years, they and colleagues at DF/HCC and elsewhere determined that the PI3K pathway is hyperactivated in many types of cancers, and also determined the causes and consequences of this hyperactivation. In a nutshell, when hyperactivated, this pathway helps cells escape the normal confines on growth and cell division, and this can both cause cancer and stimulate existing cancers.

Researchers also found that the tumor suppressor called phosphatase and tensin homolog (PTEN) normally inactivates everything that PI3K activates, as part of the natural checks and balances on cell growth. In many cancers, PTEN is defective or deleted, eliminating its protective function. Both overactive P13K signaling and loss of PTEN were later identified in glioblastoma. About 15 percent of glioblastoma patients have PI3K activation and another 45 percent lack a functioning PTEN, explains neuro-oncologist Patrick Wen, MD (DFCI).

“To date, we cannot replace a lost gene’s function,” Wen says, “so we use targeted therapies to inhibit aberrant tyrosine kinases and other signaling molecules.” Many targeted therapies can quickly shrink tumors, but tumors often return after cancer cells develop resistance. Cantley and others hypothesized that inhibiting PIK3 signaling might enhance the effect of these inhibitors and other therapies. Could PIK3 inhibition in glioblastoma, in combination with standard therapy or other new therapeutics, increase the time period before patients relapse?

Some 100 clinical trials are testing PI3K inhibitors, yet most do not cross the blood-brain barrier and so would not benefit glioblastoma. Now, a new compound, BKM120 by Novartis, does enter the brain. It is an oral pan-PI3K inhibitor that hits all relevant subunits of PI3K. Following promising pre-clinical work, José Baselga, MD, PhD (MGH), ran a phase I clinical study of this compound in all cancers, and Stiles helped with the clinical work in glioblastoma. Wen is running clinical trials testing it alone and combination with other drugs in glioblastoma patients. (See the accompanying Spotlight article about an ongoing Phase 2 trial of BKM120.) 

“It’s hard to kill glioblastoma tumors, and no one expects blocking PI3K alone will be all it takes,” says Wen. “But it’s the backbone for combination therapy, so we are focusing on what is the best combination and how to predict who will respond.”

Genetically Informed Trials

Before targeted therapies, all patients with a certain cancer type – non-small cell lung cancer (NSCLC), melanoma, glioblastoma, etc. – received the same treatment. Even after targeted therapies like imatinib (Gleevec) and gefitinib (Iressa) had proven their efficiency in subsets of cancers with a defining genetic profile, new targeted agents were still tested first in any patient with, for example, NSCLC, regardless of the whether a patient’s tumor had the genetic anomaly the drug was intended to target. As a result, if only 10 percent of NSCLC patients have the targeted mutation, the therapeutic will not help the other 90 percent of participants in the trial. Based on the poor overall results, the new agent may not gain approval, denying it to the subgroup of patients who can benefit from it – and who could be selected by their tumor’s genetic profile. Pharmaceutical companies were originally not interested in developing an expensive drug for such a small population of cancer patients, Wen says. But as evidence demonstrated the effectiveness of targeted therapies in these subgroups and as more genetic mutations defining different subtypes were discovered, the mindset began to change.

Now, a growing number of clinical trials require first genetically profiling the prospective participants’ cancers to see if they are candidates for a targeted therapy. But until recently, not enough was known about brain cancer genetic subtypes and few targeted therapies were able to cross the blood brain barrier, says Tracy Batchelor, MD, (MGH), who is a strong advocate for genetically informed trials.

“Other cancers are ahead of us, though neuro-oncology is advancing in that direction. DF/HCC has taken the first step by genetically analyzing every brain cancer patients’ tumor, upon consent, using the DFCI Oncomap and MGH SNaPshot platforms. Now we are developing glioblastoma trials with eligibility requirements that participants have a particular genetic alternation that matches up with targeted therapy being tested in the trial.”

Batchelor is leading trials testing a new inhibitor of the epidermal growth factor receptor (EGFR). Unlike in other cancers, EGFR is not usually mutated in most gliomas. Still, about 40 percent of glioblastoma tumors have extra copies of the EGFR gene, which may make the cancer more aggressive. EGFR is the most common gene amplified in glioblastoma.

An earlier trial of an EGFR inhibitor was disappointing, but a new compound, dacomitinib (PF-00299804), is more potent, irreversible, and, importantly, crosses the blood brain barrier. Batchelor opened a phase II trial of this compound for relapsed glioblastoma patients with EGFR amplification in Spring 2010. Results are still pending “This was the first trial of a targeted therapy in brain cancer that requires EGFR amplification in tumor cells in order for participants to enroll and receive the drug,” Batchelor says, and it has paved the way for more.

Smart Analysis for Smart Drug Trials

If targeted therapies are smart drugs because they “know” to select a molecular aberration that distinguishes a specific cancer cell type from other cells, genetically informed clinical trials are smart trials because they test experimental drugs only in patients whose tumors have the targeted aberration. These trials also require smart analysis. Otherwise, researchers cannot tell whether it was a fair trial of the drug or compound, explains Batchelor. If the trial was positive, did the drug make the difference? If it was negative, did the drug miss the target? Did it even cross the blood brain barrier?

Researchers want to demonstrate that the participants who do best in a clinical study are the ones where the therapeutic actually hits its molecular target in the tumor, and that it alters cancer cells in ways that explain the observed response to the therapeutic. That demonstration ideally requires serial biopsies to track the cancer cells’ changes over time, but brain tumors are far from ideal cancers for serial biopsies.

About a third of glioblastoma patients do need second surgeries to remove more tumor mass after relapse. In those cases, researchers can start the trial participants on the targeted therapy prior to the second surgery and perform analysis on the surgical tumor specimen to determine if the drug “hit” the target. For the participants not receiving a second surgery, Batchelor, Andrew Chi, MD, PhD (MGH), and Xandra Breakefield, PhD (MGH) are developing new methods for non-invasive monitoring through blood samples.

One non-invasive method looks at circulating exosomes, which are membrane-bound structures on the edges of brain tumors. “When they are pinched off of cell membranes, exosomes take some of the tumor’s genetic material with them. They circulate in the blood, so we hope to capture them to get a window on changes in the tumor over time, and some indicator of whether dacomitinib hit its target,” explains Batchelor.

Another method involves advanced in vivo imaging of blood samples, an effort led by Ralph Weissleder, MD, PhD (MGH), who creates imaging techniques for exploring disease biology and helps translate discoveries into new drugs. He developed a hand-held device that detects changes in proteins circulating in the blood and can gauge the effects of EGFR inhibition on the phosphorylation chemistry of molecules downstream of the EGFR tyrosine kinase. Batchelor and Chin will be applying both exosome analysis and in vivo imaging in the ongoing phase 2 trial of the EGFR inhibitor, dacomitinib (PF-00299804).

Much More to Learn

DF/HCC researchers still want to learn much more about genetic lesions in brain tumors and whether they might lend themselves to the design of targeted therapeutics. “We have made great progress on many fronts in neuro-oncology, but we simply don’t know enough about mutations that propel brain tumors. So we continue to genetically profile these cancers to find other genetic markers that might become significant as research progresses,” Stiles says.

As an example, he cites DF/HCC work in pediatric brain cancers. Overall, primary cancers of the brain have overtaken leukemias as the number one cause of cancer related death in children. Scott Pomeroy, MD, PhD (BCH), and his co-investigators, in collaboration with genomic sequencing researchers at the Broad Institute, very recently identified distinguishing genetic profiles for medulloblastoma tumors, a brain cancer that affects primarily children under the age of ten. The researchers found that some medulloblastoma subtypes have genetic mutations or amplification in common oncogenes. Inhibitors targeting those oncogenes are now in development, and when ones that cross the blood brain barrier become available for clinical testing, DF/HCC will take a lead in those trials too. An accompanying article, “Profiling Medulloblastoma,” discusses this new research. 

With the strategy of focusing on every aspect of research, from basic discovery through to translational and clinical work, Stiles hopes DF/HCC can soon offer more options and more personalized treatments to neuro-oncology patients, both old and young. “At DH/HCC, we are progressing toward the ultimate goal of having therapeutics that attack targets unique to a patient’s brain cancer cells and that spare normal cells. We believe this work will lead to therapies that cause fewer problematic side effects or long-term consequences for brain cancer patients, while providing them better prognoses for symptom-free survival.”

BATCHELOR REFERENCE

Chi, Andrew, Tracy Batchelor, Dora Dias-Santagata, Darrell Borger, Charles Stiles, Daphne Wang, William Curry, et al. “Prospective, High-throughput Molecular Profiling of Human Gliomas.” Journal of Neuro-Oncology 110, no. 1 (2012): 89–98.

WEN REFERENCE

Wen, Patrick Y., Eudocia Q. Lee, David A. Reardon, Keith L. Ligon, and W. K. Alfred Yung. “Current Clinical Development of PI3K Pathway Inhibitors in Glioblastoma.” Neuro-Oncology 14, no. 7 (July 1, 2012): 819–829.

FUNDING SOURCES
Research discussed in this series of articles was funded in part by the Catherine and Ben Ivy Foundation, the Pediatric Low Grade Astrocytoma (PLGA) Foundation, and the National Institutes of Health.