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Targeted therapies — state of the art
Members of the Hem/Onc Today editorial board discuss the role of targeted therapies in cancer treatment.
The FDA has indicated many agents as targeted therapies for cancer treatment during the last year, and many more are potentially on the way.
In October 2006, bevacizumab (Avastin, Genentech) was approved for first-line treatment with chemotherapy for advanced, non-squamous non–small cell lung cancer. Data published in 2007 reinforced the role of sunitinib (Sutent, Pfizer) in treating renal cell carcinoma, for which it was indicated in 2006. Also in 2007, the FDA approved lapatinib (Tykerb, GlaxoSmithKline) for metastatic breast cancer.
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Among other approvals were thalidomide (Thalomid, Celgene) for multiple myeloma, panitumumab (Vectibix, Amgen) for epidermal growth factor receptor (EGFR)–expressing colorectal cancer, and trastuzumab (Herceptin, Genentech) as adjuvant therapy for HER2–overexpressing breast cancer.
As part of this month’s focus, the Hem/Onc Today editorial board discussed where targeted therapy research is going, what seems most promising and the role of targeted therapy in cancer treatment.
The future of targeted therapies is promising, they said.
“Numerous targeted therapies — small molecules and antibodies — have proven to be effective in many different types of tumors,” said Douglas Yee, MD, director of the University of Minnesota Cancer Center in Minneapolis, and member of Hem/Onc Today’s Breast Cancer section. “In some cases, targeted therapies have shown clinical activity when conventional cytotoxic drugs have not been successful.”
The most recent example, Yee said, is the use of sorafenib (Nexavar, Bayer) for hepatocellular carcinoma. In other cases, a combination of targeted therapies with conventional cytotoxic drugs is the most effective. But conventional treatments may be considered targeted therapy on their own, Yee said.
“Broadly, targeted therapies are designed to disrupt the function of a specific molecule or molecular pathway thought to be critical for cancer cell biology,” he said. “In many ways, conventional cytotoxic therapy can be considered a targeted therapy directed toward DNA synthesis. However, other aspects of tumor biology can also be targeted. Perhaps the clearest and first example of targeted therapy is tamoxifen. By inhibiting the estrogen receptor, a nuclear transcription factor, the clinical course of breast cancer can be altered.”
Developing targeted therapies
“We are in a great place for targeted therapy development,” Brian Druker, MD, director of the Oregon Health and Science University Cancer Institute, and editor of Hem/Onc Today’s Hematology Malignancies section, said in an interview. “We’re learning more and more about the drivers of hematologic malignancies, and there are lots of compounds in development.”
The targeted therapy drug imatinib (Gleevec, Novartis) is the standard treatment for chronic myelogenous leukemia. Another agent, dasatinib (Sprycel, Bristol-Myers Squibb), was recently indicated as a second-line treatment for patients with imatinib resistance. Another second-line treatment agent, nilotinib (Novartis), is currently under FDA review, Druker said.
With many targeted therapies in development, the future is promising, Druker said.
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“What we want is to have a more thorough understanding of the abnormalities that are critical to each tumor type and have drugs that target these abnormalities,” Druker said. “We have a long way to go before we get there, but right now the opportunities and the ability to apply what we know have never been better.”
Donald L. Trump, MD, president and CEO of the Roswell Park Cancer Institute and editor of Hem/Onc Today’s Genitourinary Cancers section, said that “many new targets have been delineated and more are being found. With more targets, there are antagonists or agonists being developed.”
However, Trump said that he is reluctant to attach a special status to current targeted therapies because they are not necessarily a new phenomenon. He said there is nothing particularly good or bad about targeted therapy. It is just another type of therapy.
“To a large extent, the buzz on ‘targeted therapy’ is bogus if it is interpreted to be something new,” he said. “All therapy for all diseases have always been ‘targeted.’ For example, methotrexate targets dihydrofolate reductase, 5-fluorouracil targets thymidylate synthase and nitrogen mustard targets DNA, proteins and RNA. These drugs were developed about 60 years ago. What has changed is that the revolution in biology and molecular biology has revealed many new molecules in tumor cells, normal cells and tumor microenvironment cells whose manipulation can inhibit tumor growth.”
Future considerations
According to Maurie Markman, MD, vice president of clinical research and professor of gynecologic medical oncology at The University of Texas M.D. Anderson Cancer Center, targeted therapies do not play a major role in gynecologic cancer treatment.
“There are no data that any targeted therapy plays a role in ovarian, endometrial or cervical cancer, with the exception of bevacizumab,” Markman said in an interview. “Right now, the molecular markers that play a role in other cancers are not relevant in ovarian cancer. They may play a role in the future, but there is no evidence that targeted therapy is of any value at all.” Markman is editor of Hem/Onc Today’s Gynecologic Cancers section.
Yee said that different clinical trial designs should be adopted to test the value of targeted therapies. There are also intellectual property barriers in developing combination treatments since different pharmaceutical companies have developed drugs that potentially work better as part of a combination, rather than as a single agent.
On the clinical level, another downside is the possibility for unknown toxicities associated with interference of the target in normal cells. Trump, however, said that targeting a single molecule would likely reduce adverse effects but may cause another problem.
“I think we also run the risk for limiting the antitumor effect since often, not always, but often, more than one pathway or target is required to kill tumor cells,” Trump said.
Many of the pathways are important for normal cellular function. Yee said that since most targeted therapies affect signaling pathways, there are two important areas to understand.
“First, are there biomarkers that indicate a tumor would be either sensitive or refractory to inhibition of the pathway, and, second, are there combinations of targeted therapies that would work in a synergistic fashion?” Yee said.
Targeted therapies are approved for specific indications, and, as with cytotoxic drugs, there will be off-label use, Yee said. Clinical trials are necessary to test the efficacy of the off-label indications, especially with the potential for unknown toxicity and the lack of predictive biomarkers, he said.
“I believe that the only way we will make progress in this area is to design and enroll patients in clinical trials that will test whether or not the specific target or targets are relevant to any given cancer,” Yee said. “By performing these trials, we will be better positioned to offer the most effective and safe care for our patients.” – by Emily Shafer and Paul Burress