Individualizing cancer therapy

Abstract

In this issue of Leukemia and Lymphoma, Ngo and colleagues describe the predictive value of cyclin D1 expression as a predictor of bortezomib response in multiple myeloma. The ability to predict treatment response based on genetic expression would be of value, if it could be confirmed in a larger study. The present publication should be considered hypothesisgenerating, but the concept of having a diagnostic test that can predict a response to bortezomib as opposed to an empiric trial of therapy is potentially useful. The response rate reported in this paper is unusually high, and there is lack of a suitable control group [1]. Whether cyclin D1 predicts responsiveness to bortezomib specifically, or is a general indicator of good prognosis, would need to be verified in a group of patients treated with melphalan-based or immunomodulatory drug (IMiD)-based therapy. Cyclin D1 is a protein that, in humans, is encoded by the CCND1 gene. The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by protein abundance throughout the cell cycle. Cyclins function as regulators via cyclin-dependent kinases. Different cyclins exhibit distinct expression, which contributes to the temporal coordination of a mitotic event. Cyclin D1 forms a complex with and functions as a regulatory subunit of cyclin-dependent kinase-4 or cyclin-dependent kinase-6, whose activity is required for cell cycle transition. Cyclin D1 interacts with tumor suppressor protein RB, and the expression of CCND1 is regulated positively by RB found on chromosome 17. Mutations, amplification, and overexpression of cyclin D1, which alters cell cycle progression, is observed frequently in a variety of tumors, and has been felt to contribute to tumorigenesis. Overexpression of cyclin D1 is not limited to myeloma, but has also been implicated in the pathogenesis of a variety of hematologic neoplasias such as mantle cell lymphoma, hairy cell leukemia, and B cell lymphoma, as well as in other solid benign and malignant tumors including parathyroid adenomas and breast, lung, and colon carcinomas. The expression of cyclin D1 is subject to both transcriptional and post-transcriptional regulation [2], and different pathways assume a dominant role in regulating its expression. This regulation can contribute to overexpression of cyclin D1 in the genesis of tumors, while nuclear factor kB (NFkB) pathways regulate cyclin D1 gene transcription. Other groups have described the favorable impact of cyclin D1 overexpression on bortezomib responsiveness. In breast cancer, cyclin D1 repression of STAT-3 expression may explain the association between cyclin D1 overexpression and improved outcome in breast cancer. Bortezomib can amplify the pro-apoptotic function of cyclin D1, and may explain why increased expression can predict response to the drug. Conversely, tumors that fail to express cyclin A have been implicated as independent markers of tumor progression and poor response to chemotherapy in advanced head and neck cancers [3]. The concept of using gene expression to individually tailor treatment specifically for cancer patients or to predict the toxicity of therapies has been a long sought after but thus far elusive goal. Gene expression profiling has demonstrated that the ability to