September 2, 2009 — A novel anticancer therapy that acts as an inhibitor of the hedgehog pathway has sparked quite a bit of excitement among experts. Although the clinical results come from a phase 1 trial, the responses that have been seen in some patients have been dramatic, and this approach has "tremendous potential," says Andrzej Dlugosz, MD, Poth Professor of Cutaneous Oncology at the University of Michigan in Ann Arbor.
Dr. Dlugosz, coauthor of an editorial published online September 2 in the New England Journal of Medicine accompanying 2 papers detailing the clinical results, explained in an interview with Medscape Oncology why there is so much excitement over this approach.
The hedgehog signalling pathway, which has been known to be involved in cancer for about 13 years, is an important regulator of the embryonic development that becomes reactivated in cancer, and might not be required in most normal adult tissues, he explained. So the hope is that inhibition of this pathway would offer a selective way of attacking just the tumor cells.
The early results suggest that this is the case, he said. Some of the responses to treatment were dramatic, and the drug that was used (GDC-0449, under development by Genentech) appears to be free from hematological toxicity. In addition, it is convenient to use, taken orally once daily.
However, Dr. Dlugosz acknowledged that these clinical results are very early — 1 of the studies published in the New England Journal of Medicine reports results from a phase 1 trial of 33 patients with basal cell carcinoma; the other is a case report of a single patient with metastatic medulloblastoma.
These 2 types of cancer are driven by the hedgehog pathway, and the cancers appear to be driven by a mutation that leads to the activation of the pathway within the tumor cells themselves, known as cell autonomous activation.
The dramatic responses that were seen in these 2 cancers suggest that they really are dependent on the hedgehog pathway, which appears to be required for the maintenance of these tumors, Dr. Dlugosz explained. "It suggests that blocking this pathway shuts down the machinery needed to keep these tumors growing," he added.
This has been seen before — with imatinib (Gleevec) in the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. This is an example of a drug targeting a critical molecule in a cancer pathway, he noted. In this case, there have been huge clinical benefits for patients, and imatinib has been hailed as revolutionizing the treatment of these cancers, as previously reported by Medscape Oncology.
However, there are many other cancers in which the hedgehog pathway is thought to play a role, possibly as many as 30% of all human malignancies, Dr. Dlugosz continued. They include pancreatic, gastrointestinal, colorectal, ovarian, prostate, some leukemias, and multiple myeloma. In many of these internal tumors, the cancer is driven by the production of a hedgehog protein that is secreted and affects the surrounding cells. They, in turn, secrete various proteins to create an environment that is nourishing to the tumor, allowing it to grow, he explained. In this case, the secreted hedgehog protein acts like a "fertilizer," he added.
There is hope, and substantial experimental data to support this hope, that the inhibition of the hedgehog pathway will be useful in the treatment of some of these cancers, perhaps alongside conventional treatment, Dr. Dlugosz said.
However, he added, at present "we have no idea ultimately how useful clinically these drugs are going to be."
Further trials are now ongoing. Genentech has a phase 2 trial in basal cell carcinoma underway, and several other companies are testing hedgehog pathway inhibitors in cancer, including Infinity and Bristol-Myers Squibb. There are also some investigator-initiated trials in progress, including 1 in children with medulloblastoma and 1 in pancreatic cancer.
Results in Basal Cell Carcinoma
The basal cell carcinoma study published online September 2 in the New England Journal of Medicine was conducted by Daniel von Hoff, MD, from the Translational Genomics Research Institute in Scottsdale, Arizona, and colleagues, including several employees of Genentech. The 33 patients were part of a larger phase 1 trial of GDC-0449, which enrolled 68 patients with a variety of solid tumors that were refractory to standard therapy, the researchers explain.
Basal cell carcinoma is usually treated with surgery, and rarely recurs or spreads, the researchers note. However, the patients in this study had advanced tumors that were no longer responding to conventional treatment options, including surgery, radiotherapy, and systemic therapy, they add.
Among the 33 patients, 18 had metastatic disease and 15 had locally advanced disease. They received the experimental drug at 1 of 3 doses (17 patients received 150 mg/day, 15 received 270 mg/day, and 1 received 540 mg/day), and the median duration of treatment was 9.8 months.
An objective response was seen in 18 of 33 patients — 2 had a complete response and 16 had a partial response, Dr. Von Hoff and colleagues report. Among the remaining 15 patients, 11 patients had stable disease and 4 progressed.
Adverse events possibly related to treatment include fatigue (in 4 patients), hyponatremia (2 patients), muscle spasm (1 patient), and atrial fibrillation (1 patient). There was 1 case of a grade 4 adverse event (asymptomatic hyponatremia), but this was judged to be unrelated to the drug, the group reports. One patient, who had locally advanced tumors and a partial response, decided to discontinue treatment after 8 months because of ongoing adverse effects (grade 1 abdominal pain, fatigue, weight loss, dysgeusia, and grade 2 anorexia).
The researchers also performed molecular studies, which, together with the responses seen, suggest that "advanced tumors rely on activation of the hedgehog pathway for growth and maintenance."
"Our findings confirm the participation of the hedgehog pathway in basal cell carcinoma and suggest that inhibition of the hedgehog pathway can be useful in treating inoperable tumors," they conclude.
Dr. Dlugosz told Medscape Oncology that although the number of patients with inoperable or metastatic basal cell carcinoma — such as those in this study — is very small, basal cell carcinomas as a group are the most common cancers in humans. Using a systemic treatment for typical basal cell carcinoma might not be justifiable because they are nearly always cured by surgery, but a topical formulation of a hedgehog pathway inhibitor, if effective, could be useful for a large number of patients. In particular, patients with these tumors on their faces — which is a common site — have said that they would be keen to avoid surgery.
However, he added, genetic studies in mice suggest that these drugs would reduce the size of the tumor, but might not eliminate it completely, meaning that some surgery would be necessary, but it would be much less invasive, he noted. The responses described in this trial are "impressive, with some massive tumors shrinking away to nearly nothing," Dr. Dlugosz remarked.
Dramatic Response in Medulloblastoma
Also published online September 2 in the New England Journal of Medicine is a case report detailing the response in metastatic medulloblastoma, described by Charles Rudin, MD, PhD, from the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, in Baltimore, Maryland, and colleagues, several of whom are employees of Genentech.
The patient was a 26-year-old man who had been diagnosed 4 years previously with medulloblastoma, which was, at the time, confined to the cerebellum. He was treated with surgery, radiation, and chemotherapy, but 2 years later showed recurrent and metastatic disease and was again treated with chemotherapy. Eighteen months later, he had widespread systemic metastatic disease, and again was treated with surgery, radiation, and chemotherapy, and with bevacizumab (Avastin).
The patient was enrolled in a phase 1 trial of GDC-0449 because there were no other therapies and because preclinical evidence suggested that hedgehog signalling could be critical in medulloblastoma, the researchers explain.
"The tumor had a remarkable, though incomplete, and rapid, though transient, response," the researchers explain. After a month of treatment, some of the tumors regressed so that 2 sternal masses were no longer palpable, supraclavicular lymphadenectomy was markedly diminished, and an epidural mass was no longer detectable.
"Within a few weeks of the treatment, the drug had a remarkable effect on the patient," Dr. Rudin said in a statement. "He went from being nearly bedridden with significant pain to exercising and having no pain."
However, after approximately 3 months of therapy, a positron emission tomography scan showed evidence of tumor regrowth at some sites, and also some new lesions. The patient stopped taking the drug because of disease progression, and despite subsequent therapies, died 2 months later.
Dr. Rudin and colleagues note that the regression "is notable because of the tumor burden and the extent of metastasis in this patient." This response "underscores the primary role that the hedgehog pathway played in maintaining and driving the growth of this patient's tumor."
"Cautious application of these initial observations through carefully monitored clinical trials involving a broad spectrum of patients with medulloblastoma is warranted," they conclude.
Dr. Dlugosz said that, unfortunately, in this case, although the tumor responded initially, it appeared that over time the tumor cells developed mutations or, through some other mechanism, acquired resistance to the drug. This has also been seen with responses to imatinib in chronic myeloid leukemia and gastrointestinal stromal tumors, he noted; in some cases, the tumors become resistant, but approaches have been developed to bypass this problem. "The genome of a typical cancer cell is very unstable, so mutations may arise, leading to resistance to therapies targeting a single key molecule in a cancer pathway," he explained. However, there is hope that new drugs can be developed to overcome this, he added, as has been the case with imatinib. In addition, in internal cancers, the hedgehog pathway is acting in nontumor cells, which might be less likely to develop mutations that lead to drug resistance.
The transformation in this tumor that made it become resistant to the hedgehog inhibitor is detailed in a paper due to be published online on September 3 in Science Express. When the cancer recurred, it had acquired a mutation in a gene that encodes the target of the drug, which prevented the drug from binding to its target.
Dr. Dlugosz reports receiving consulting fees from Merck and grant support from Pfizer. Dr. Rudin, Dr. Von Hoff, and a coauthor, Dr. LoRusso, report receiving research funding from Genentech for a GDC-0449 phase 1 trial. Some of the coauthors on both papers are Genentech employees.
N Engl J Med. Published online before print September 2, 2009.
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