Michael Ford MD
Faculty Peer Reviewed
Last spring, The New York Times published a series of articles that examined the status of “the War on Cancer,” initiated some 40 years ago by then president Richard Nixon[1]. The halting pace of this war was made more poignant with the recent death of Senator Edward M. Kennedy, who had championed the effort from its inception[2]. Certainly, much has been learned about cancer in the intervening decades, but while other illnesses saw dramatic improvement in outcome (since 1950, deaths from stroke per 100,000 have plummeted 74%, and deaths from heart disease and influenza and pneumonia each decreased about 60%) the national death rate per 100,000 for cancer declined by only 5%[1]. Indeed, one of the few unqualified successes in cancer treatment is the discovery that most cases of chronic myelogenous leukemia (CML) occur as a result of a chromosomal translocation that creates a fusion gene, Bcr-Abl, on which the malignant cell is dependent for survival. Gleevec and other second and third generation drugs that interfere with the intracellular tyrosine kinase that results from this fusion have changed the prognosis of CML from grim to one of the best in cancer.
Enzymes like Bcr-Abl- ones that are active only in malignant cells, are integral to the propagation of the malignancy, and can be effectively inhibited- are the Holy Grail of cancer biology, as their discovery renders a particularly recalcitrant problem one more akin to treating a bacterial infection with an antibiotic. But, because malignant cells derive from the host organism, finding pathways that meet these criteria has proved difficult. The Hedgehog signaling pathway was discovered in 1980 by Christiane Nüsslein-Volhard and Eric Wieschaus in their studies of the molecular events that control segment polarity in developing Drosophila larvae; the pathway was subsequently found to have its homologue in vertebrates, including humans.Hedgehog is thus active throughout embryogenesis, but is not expressed in the majority of adult tissues. It is activated in a wide range of cancers, including gastrointestinal tumors, prostate cancer, hematological malignancies, and gliomas. This has led to great enthusiasm that inhibition of the pathway at any number of integral steps may offer hope for effective and precise cancer-specific cell killing accompanied by a much improved side-effect profile compared with traditional cancer therapies[3]. Already, multiple small molecule inhibitors of the Hedgehog signaling pathway have been pulled from compound libraries. The first to be tested in a Phase I trial is GDC-0449, a novel orally available small molecule inhibitor of SMO, the transmembrane protein that initiates activation of the Hedgehog pathway. In next week’s New England Journal of Medicine, a multi-institution group will report on the use of GDC-0449 in the treatment of advanced basal cell carcinoma[4] and metastatic medulloblastoma[5], with encouraging results.
The first paper involves 33 patients with locally advanced unresectable or metastatic basal cell carcinoma.B asal cell carcinoma is the most common skin cancer in the United States. Most cases are completely cured with surgical resection, while a small minority demonstrate progression to unresectable or metastatic disease.For these unfortunate patients, the median survival is approximately eight months. Most basal cell carcinomas harbor mutations that lead to ligand-independent, constitutive activation of the Hedgehog signaling pathway, suggesting a possible means by which to inhibit these tumors. Of 18 patients in the study with metastatic basal cell carcinoma, a 50% response to GDC-0449 was seen (nine patients had a partial response, seven had stable disease, and two progressed) and in 15 patients with locally advanced disease there was a 60% response rate (two complete responses, seven partial responses, four patients with stable disease, and two who progressed). The median time of study participation at data cutoff was 9.5 months, and the median time of response was 8.8 months and ongoing, already surpassing the median expected 8-month survival in this group had they received no treatment. No dose-limiting toxicities were encountered[4].
In a second paper, the case report of a young man with malignant medulloblastoma is presented. Medulloblastoma is the most common malignant brain tumor of childhood. The mainstays of treatment are surgical resection followed by radiation and chemotherapy; the median survival for patients with recurrent disease after such treatment is less than six months, with a dismal two-year survival of approximately 9%. A minority of medulloblastomas (30%) is characterized by ligand-independent constitutive activation of the Hedgehog signaling pathway, suggesting that inhibition of this pathway may be of therapeutic benefit. The 26 year old patient presented in this case report had metastatic disease despite multiple previous treatments including surgery, radiation, chemotherapy and several newer biological treatments, and confirmed supranormal levels of Hedgehog pathway activation. After receiving GDC-0449 for less than one month, he was found to have objectively decreased lymphadenopathy and his considerable pre-trial pain had decreased to zero. After two months of therapy, he had no remaining palpable lymphadenopathy and no pain. He had returned to his pre-morbid levels of physical activity and gained seven kilograms. He also had decreased FDG avidity on PET scan at all previous sites of disease. Unfortunately, a scheduled PET scan at three months showed markedly increased FDG avidity at some lesions and apparent tumor regrowth at some sites. He was removed from the study secondary to disease progression and died five months after beginning therapy. However, given his extensive involvement with metastatic disease (CNS with epidural involvement, extensive lymphadenopathy and bone metastases, and likely involvement of his bone marrow), his response was remarkable. It was postulated that his rapid loss of response may have reflected development of resistance to the small molecule inhibitor, similar as is seen with Gleevec used to inhibit the Bcr-Abl kinase[5]. In fact, this assumption was proved to be correct. In an article published in Science, the mutational status of the young man’s Hedgehog pathway proteins was examined after he was treated with GDC-0449 and a single new (compared with pre-treatment) point mutation was discovered in SMO that prevented GDC-0449 from binding to the transmembrane protein SMO, but did not prevent SMO from activating the downstream Hedgehog pathway[6].
Finally, in this week’s issue of The New England Journal, Mardis and coworkers report the use of an emerging technology, massively parallel DNA sequencing. This cost-efficient and rapid method was used to define a “rough draft” of the entire genome of a 38 year old man’s cytogenetically normal AML clone[7]. AML is a clonal hematopoietic malignancy caused by both inherited and acquired mutations in the genome. Hematologists typically analyze the karyotype of an individual patient’s AML clones, and cytogenetic abnormalities are among the most powerful predictors of response to treatment. Not a small number of patients have cytogenetically normal malignant clones, however. In comparison of this genome with that of one of the same patient’s genotypically normal skin cells, the researchers were able to identify approximately 750 mutations specific to the AML clone, of which only a handful of novel mutations were predicted to influence gene expression; four of these were also found in AML clones from other patients, supporting their role in disease pathogenesis[7].
Taken together, these papers offer hope for the future of cancer drug development. The first two papers demonstrate the integral role of Hedgehog signaling in some cancers, and the ability of an orally available small molecule to inhibit this signaling and halt or slow growth of the cancer. Hedgehog can thus be added to Bcr-Abl as a pathway unique to cancer cells, the inhibition of which can be accomplished with much more tumor specificity, and much less systemic toxicity, than standard chemotherapy. The development of resistance to the drug in one case should not be automatic cause for dismay; this, too, has a parallel in the example of CML, where second and third generation Bcr-Abl kinase inhibitors have offered effective therapy well beyond the occurrence of resistance to Gleevec. The third paper harnesses the impressive power of new DNA sequencing technologies to look at the entire genome of an AML clone. This type of approach, which does not rely at all on pre-conceived notions about the biology of the particular cancer, offers optimism that more of these elusive cancer-specific pathways indeed exist, and will be found in the future.
Dr. Ford is a 2nd year internal medicine resident at NYU Medical Center.
Peer reviewed by Sandeep Mangalmurti, MD JD, Chief Resident, NYU Department of Medicine
1. Kolata “Advances Elusive in the Drive to Cure Cancer” NYT April 23, 2009, Page A1. (http://www.nytimes.com/2009/04/24/health/policy/24cancer.html?scp=7&sq=war+on+cancer&st=nyt)
2. Kolata & Altman “Weighing Hope and Reality in Kennedy’s Cancer Battle” NYT April 27, 2009, Page A1. (http://www.nytimes.com/2009/08/28/health/28brain.html?_r=1&scp=13&sq=cancer&st=cse)
3. Jiang J & Hui C “Hedgehog Signaling in Development and Cancer” Dev Cell. 2008 Dec;15(6):801-12.
(http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WW3-4V3K6DM-5&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=458409c66d3288bd85aa5c6f22cf3ff8)
4. Von Hoff et al “Inhibition of the Hedgehog Pathway in Advanced Basal-Cell Carcinoma” N Engl J Med. 2009 Sep 2. (Epub ahead of print)
(http://content.nejm.org/cgi/content/full/NEJMoa0905360v1)
5. Rudin et al” Treatment of Medulloblastoma with Hedgehog Pathway Inhibitor GDC-0449″ N Engl J Med. 2009 Sep 2. (Epub ahead of print)
(http://content.nejm.org/cgi/content/full/NEJMoa0902903v1)
6. Yauch RL et al “Smoothened Mutation Confers Resistance to a Hedgehog Pathway Inhibitor in Medulloblastoma” Science. 2009 Sep 2. (Epub ahead of print)
(http://www.sciencemag.org.ezproxy.med.nyu.edu/cgi/content/abstract/1179386v1)
7. Mardis et al “Recurring mutations found by sequencing an acute myeloid leukemia genome” N Engl J Med. 2009 Sep 10;361(11):1058-66.
(http://content.nejm.org/cgi/content/full/361/11/1058)