Targeted therapies improve cancer treatment

The revolution in medicine brought about by greater understanding of genomics has led to a number of targeted therapies in cancer care.

The basic concept is to first find the genomic change or mutation that leads to a disease, then learn its gene product and then develop a drug that inhibits the action of the aberrant gene product. The first was imatinib (Gleevec) for chromic myelocytic leukemia (CML.) When a translocation occurs that changes the normal ABL gene on one chromosome with the addition of a segment of the normal BCR gene that comes from a different chromosome, the result is a modified tyrosine kinase called BCR-ABL kinase that leads to CML. Imatinib blocks the action of the BCR-ABL tyrosine kinase thus reversing the disease.

This drug has made a quantum change in the treatment of CML and in the quality of life for these patients. But some patients’ cells develop resistance to imatinib which led to the development of new tyrosine kinase inhibitors (dasatinib and nilotinib.) Not only are they useful when resistance develops, these new agents have been found to not only be effective for relapsed CML patients but also more effective as first line treatment with more patients having a complete cytogenetic response and a higher rate of major molecular response. So they represent a further advance based the concept of targeted therapy.

Crizotinib (Xalkori, produced by Pfizer) at first appeared to be of minimal value in lung cancer. A few patients responded, some rather nicely, but the vast majority had no response at all. Then it was appreciated that about one in 20 patient’s tumors had a variation in a gene called ALK due to a chromosomal rearrangement. This altered gene in turn directs the creation of a protein kinase found in these patients’ lung cancer cells. Crizotinib inhibits this protein and it was these patients and only these patients that were the responders. In these few who have the ALK mutation, about 90% have good responses. This means that about 10,000 Americans with lung cancer each year could benefit from this new compound. It was approved by the FDA with the proviso that it be used only for those lung cancer patients proven to have the rearranged gene.

A mutation in the BRAF gene occurs in some patients with tumors of the colon, melanoma and other cancers. BRAF mutations have been found to be a valuable prognostic marker in colon cancer. BRAF status is strong predictor of outcome to therapy; in one large study, those with BRAF mutations survived about 8 months compared to 25 months for those without a BRAF mutation. Cetoximab (Erbitux) offers added benefit to chemotherapy in metastatic disease. Responses are better for those without the BRAF gene mutation. And for those patients that are also KRAS (another gene often mutated in colon cancer) mutation negative, the outcomes were better still. Further it was found that those whose tumors had the BRAF mutation had a shorter response duration and a shorter survival.

BRAF mutations in melanoma are common and have led to the development of a few targeted drugs that have excited oncologists during this year as results have become available from large clinical trials. Although not curative and certainly not panaceas, a new monoclonal antibody and a new drug that inhibits the protein products of BRAF gene mutations are having a surprisingly good effect. One of the new targeted drugs is an inhibitor of the BRAF mutated gene product called Vemurafenib . Vemurafenib (Zelboraf) decreased the relative risk of death by 63% and the risk of tumor progression by 74% when combined with dacarbazine (an alkylating agent also known as DTIC or imidazole carboxamide which has been the long time standard of care for metastatic melanoma) compared to dacarbazine alone in a large cohort of patients with the BRAF V600E mutation in their melanoma. The FDA approved this drug for treating melanoma in August, 2011 for BRAF mutation positive patients. The cost, according to the manufacturer, Genentech, will be about $60,000 for a course of therapy over about six months. That is a lot of money for a non-curative drug but still it is a major improvement and offers real benefits and hope to patients, a testament to the concept of targeted therapy based on genomic information

Another drug, ipilimumab (Yervoy) also has shown substantial activity against metastatic melanoma. It is a monoclonal antibody that acts to enhance T-cell activation. In a large clinical trial, patients with metastatic melanoma were randomized to ipilimumab plus dacarbazine or dacarbazine alone. Those who received the monoclonal antibody had a longer time of progression free survival and the responses that developed persisted longer (19.3 vs. 8.1 months) than those who received dacarbazine alone. Overall survival was statistically but probably not all that much different at 11.2 months compared to 9.1 months but there were about 25% alive at four years which is quite noteworthy. Manufacture by Bristol Meyers Squibb, it was approved by the FDA in March, 2011 with caveats on observing for and managing side effects. The price is about $120,000 for a course of therapy.

Another targeted drug that is not genomically based is sipuleucel-T (Provenge.) This is the first licensed therapeutic vaccine. It was found in prostate cancer patients who were unresponsive to hormonal therapy and were heavily pretreated that Provenge modestly improved survival (25.8 months compared to 21.7 months for the placebo group). This vaccine is made by taking the patients own lymphocytes and augmenting them in the laboratory to react to the tumor antigen, hence it can be called a “personalized vaccine.” Although the improved survival was limited, it is exciting to finally have an immune therapy that has a beneficial effect; this will ignite others to improve on this concept. Further, although not approved for this use, it may well be that the vaccine will be found to have an even greater activity if used with patients who are not heavily pretreated. Meanwhile it is well to understand that it, like many new oncology drugs, is exceptionally expensive (about $93,000) raising the question of whether it (and some of the other new expensive compounds) is worth the expense for a rather minimal extension of life.

The bottom line is that these targeted drugs can be quite effective in some cancer patients but the costs are also quite substantial.

Stephen C. Schimpff is an internist, professor of medicine and public policy, and former CEO of the University of Maryland Medical Center. He is the author of The Future of Medicine — Megatrends in Healthcare and blogs atMedical Megatrends and the Future of Medicine.

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Gregory Pawelski
Although the theory behind targeted therapy is appealing, the reality is more complex. For example, cancer cells often have many mutations in many different pathways, so even if one route is shut down by a targeted treatment, the cancer cell may be able to use other routes.In other words, cancer cells have ‘backup systems’ that allow them to survive. The result is that the drug does not shrink the tumor as expected. One approach to this problem is to functionally target multiple pathways in a cancer cell.Another challenge is to identify which of the targeted treatments will be effective (enzyme inhibitors, proteasome inhibitors, angiogenesis inhibitors, and monoclonal antibodies).Targeted therapy is still trial-and-error treatment.The functional profiling platform can explore multiple signaling pathways from the same test. It doesn’t have to test for each and every signaling pathways there are.There are many pathways to altered cellular function. Testing for these pathways, those which identify DNA, or RNA sequences or expression of individual genes or proteins often examine only one component of a much larger, interactive process. In testing for all “known” mutations, if you miss just one, it may be the one that gets through.And it’s not just only targeted drugs that may be effective as first-line treatment on your individual cancer cells. Cancers share pathways across tumor types. There really is no lung cancer chemos, or breast cancer chemos, or ovarian cancer chemos.There are chemos that are sensitive (effective) or there are chemos that are resistant (ineffective) to each and every “individual” cancer patient, not populations. There are chemos that share across tumor types.The functional profiling platform has the unique capacity to identify all of the operative mechanisms of response and resistance by gauging the result of drug exposure at its most important level: cell death.Finding what targeted therapies would work for what cancers is very difficult. A lot of trial-and-error goes along trying to find out. However, finding the right targeted therapies for the right “individual” cancer cells can be improved by cell-based assays, using functional profiling.Identifying DNA expression of individual proteins (that measure of RNA content, like Her2, EGFR, KRAS or ALK) often examine only one component of a much larger, interactive process. Gene (molecular) profiling measures the expression only in the “resting” state, prior to drug exposure. There is no single gene whose expression accurately predicts clinical outcome. Efforts to administer targeted therapies in randomly selected patients often will result in low response rates at significant toxicity and cost.Functional profiling measures proteins before and after drug exposure. It measures what happens at the end (the effects on the forest), rather than the status of the individual trees. Molecular profiling is far too limited in scope to encompass the vagaries and complexities of human cancer biology when it comes to drug selection. The endpoints of molecular profiling are gene expression. The endpoints of functional profiling are expression of cell death (both tumor cell death and tumor associated endothelial [capillary] cell death).In testing for all “known” mutations, if you miss just one, it may be the one that gets through. And it’s not just only targeted drugs that may be effective as first-line treatment on your “individual” cancer cells. Cancers share pathways across tumor types.Targeted treatments take advantage of the biologic differences between cancer cells and healthy cells by “targeting” faulty genes or proteins that contribute to the growth and development of cancer. Many times these drugs are combined with chemotherapy, biologic therapy (immunotherapy), or other targeted treatments.Clinicians have learned that the same enzymes and pathways are involved in many types of cancer. However, understanding targeted treatments begins with understanding the cancer “cell.” In order for cells to grow, divide, or die, they send and receive chemical messages. These messages are transmitted along specific pathways that involve various genes and proteins in the cell.Cancer cells often have many mutations in many different pathways, so even if one route is shut down by a targeted treatment, the cancer cell may be able to use other routes.Targeted therapies are typically not very effective when used singularly or even in combination with conventional chemotherapies. The targets of many of these drugs are so narrow that cancer cells are likely to eventually find ways to bypass them.Physicians may have to combine several targeted treatments to try an achieve cures or durable responses for more complicated tumors like those that occur in the breast, colon and lung.These targeted therapies produce limited results because they can help a relatively small subgroup of cancer patients. But when they work, they produce very good responses. With targeted therapy, the trick is figuring out which patients will respond. Tests to pinpoint those patients cannot be accomplished with genetic testing.All the gene amplification studies, via genetic testing, tell us is whether or not the cancer cells are potentially susceptible to a mechanism/pathway of attack. They don’t tell you if one drug is better or worse than another drug which may target a certain mechanism/pathway. Cell-based functional analysis can accomplish this.The cell is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions. You need to analyze the systems’ response to drug treatments, not just one target or pathway, or even a few targets/pathways.Literature Citation:Functional profiling with cell culture-based assays for kinase and anti-angiogenic agents Eur J Clin Invest 37 (suppl. 1):60, 2007Functional Profiling of Human Tumors in Primary Culture: A Platform for Drug Discovery and Therapy Selection (AACR: Apr 2008-AB-1546)

Targeted therapies improve cancer treatment

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