Crossing Therapeutic Boundaries: Molecular Profiling May Help Move Noncancer Drugs Into Oncology Settings

Publication
Article
Oncology Live®October 2014
Volume 15
Issue 10

One of the most striking changes in our understanding of the fundamental biology of malignant disease has been the observation that "driver" molecular abnormalities may frequently cross major histologic barriers.

Maurie Markman, MD

Editor-in-Chief of OncologyLive

Senior vice president for Clinical Affairs and National Director for Medical Oncology Cancer Treatment Centers of America, Eastern Regional Medical Center

One of the most striking changes in our understanding of the fundamental biology of malignant disease has been the observation that “driver” molecular abnormalities may frequently cross major histologic barriers.

Consider the now classic example of the essentially identical genetic mutation that characterizes the progression of the hematologic malignancy chronic myeloid leukemia (CML) and the solid tumor gastrointestinal stromal sarcoma (GIST). In these two vastly different malignant conditions, the same drug (imatinib) that favorably impacts the natural history of the hematologic cancer produces a similarly impressive result when employed in the treatment of the solid tumor.

Another example, while clearly not as clinically spectacular as the CML/GIST relationship, is the finding of HER2 overexpression in breast, gastric, and non—small cell lung cancers, and in small subsets of patients with lymphoma. In this case, the administration of trastuzumab has been shown to be of clinical utility in all four malignant histologies.

In these settings, the presence of a unique molecular abnormality has suggested the clinical utility of an antineoplastic drug previously demonstrated to be of use and approved by the drug regulatory agencies for administration in another tumor type (eg, trastuzumab in breast cancer being employed in HER2-positive gastric cancer).

But is it possible that molecular profiling could help identify pharmaceutical agents approved for conditions not related to cancer that have the potential to interfere with a specific “driver” molecular abnormality in a given cancer? And, might this theorized interaction between the drug and the target ultimately be revealed to favorably impact the natural history of the cancer?

Small Study Shows Potential

Consider, for example, the fascinating preliminary data regarding a potential role for itraconazole in the management of patients with the rare but serious condition of advanced or metastatic basal cell carcinoma.1 Although basal cell cancers are the most common of all human malignancies, fortunately only 2% will be advanced or ultimately become metastatic.

Preclinical data have revealed the importance of the hedgehog signaling pathway in the biology of essentially all basal cell cancers.2 Vismodegib, which interferes with a major component (smoothened) in the hedgehog pathway, is the first and thus far only FDA-approved agent targeting this network. It has produced objective response rates of 43% in locally advanced basal cell cancers and 30% in metastatic disease, confirming the substantial clinical relevance of this pathway.2

To search for other agents that might effectively target the hedgehog pathway, a research team led by Stanford University scientists screened a library of approximately 2400 FDA-approved or post-phase I drugs for responses to a known signaling protein in the network.3 They determined that itraconazole, a widely utilized antifungal agent, was an attractive candidate and characterized its cell-signaling activity on a molecular level through mouse experiments.3

Reasoning that itraconazole had a well-defined safety profile in human patients after nearly 25 years of study and clinical use,3 the research team explored its potential in a phase II trial.1 A total of 19 patients with advanced, nonmetastatic basal cell carcinoma received itraconazole in a trial designed to explore as a primary endpoint the biological activity of the agent in this clinical setting.1 The study revealed that cell proliferation, hedgehog pathway activity, and the overall tumor area were reduced by 45%, 65%, and 24%, respectively, following administration of this nontraditional “antineoplastic” pharmaceutical drug. Further, of eight patients with multiple nonbiopsied tumor masses, four achieved a partial response and four had stable disease. By contrast, patients with advanced basal cell carcinoma who were observed without being treated with itraconazole (n = 10), or had previously received vismodegib prior to the administration of itraconazole (n = 3), showed no change in tumor size.

Although advanced or metastatic basal cell carcinoma is a most uncommon clinical entity, this study represents a limited sample size even within the relatively rare malignancy. As a result, it would be inappropriate to draw any conclusions regarding the potential utility of itraconazole in patients previously managed with vismodegib based on this study. Therefore, the overall clinical utility of itraconazole in advanced or metastatic basal carcinoma remains to be defined.

However, this report provides provocative and solid data in support of the concept that pharmaceutical agents currently and previously used in clinical practice outside the oncology arena may produce meaningful clinical effects if preclinical efforts demonstrate their potential impact on relevant molecular targets present within individual cancers. Additional research efforts in this domain are clearly indicated.

Maurie Markman, MD, editor-in-chief, is president of Medicine & Science at Cancer Treatment Centers of America, and clinical professor of Medicine, Drexel University College of Medicine. maurie.markman@ctca-hope.com.

References

  1. Kim DJ, Kim J, Spaunhurst K, et al. Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma [published online February 3, 2014). J Clin Oncol. 2014;32(8):745-751.
  2. Sekulic A, MIgden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366(23):2171-2179.
  3. Kim J, Tang JY, Gong R, et al. Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell. 2010;17(4):388-399.

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