Thursday, August 14, 2014
Friday, July 25, 2014
A recent paper* summarized the history of oncology drug discovery and analyzes the contibutions of phenotypic drug discovery vs traditional target-based drug discovery. The authors analyze the development and mechanisms of all small molecule-based cancer drugs approved by the FDA over the past 15 years and those currently in clinical development.
The authors show that the majority of small molecule inhibitors for oncology originated in target-based discovery. However, a significant number of inhibitors were identified in phenotypic drug screening approaches. The authors suggest that the rate-limiting step in bringing compounds identified in phenotypic screenings into clinical development is the lack of mechanistically defined cellular models for the cancer phenotypes in question and also the reliance on traditional drug effects such as cytotoxicity and mitotic arrest, which are only a component of the hallmarks of cancer.
The authors suggest that mechanistically informed phenotypic models may better enable compounds identified in phenotypic screenings to successfully complete clinical development. These models would enable confirmation that the targeted agents have a molecular mechanism of action, which would enable PD biomarker development and development of diagnostic hypotheses and patient tailoring hypotheses.
* Moffat, et. al. (2014) Phenotypic screening in cancer drug discovery — past, present and future. Nat Rev Drug Discovery, doi:10.1038/nrd4366
Wednesday, July 23, 2014
A recent paper* has reported a direct biological link between cholesterol and cancer. The Wnt pathway plays an important role in cancer formation and metastasis, particularly in colorectal cancer in which the Wnt-related gene APC is frequently mutated. In this report, the authors find that cholesterol is enriched around the Wnt-related Frizzled and LRP5/6 receptors in cancer cells. This suggested to the authors that perhaps cholesterol itself could activate Wnt signaling. The authors found that cholesterol directly recruits the Wnt-related Dishevelled (Dvl) scaffold protein to the cell membrane through interaction with its PDZ domain. Dvl then activates the canonical Wnt signaling pathway. In this way, cholesterol may directly regulate activation of canonical Wnt signaling and may regulate balance between canonical and non-canonical signaling. Future studies will be needed to determine effects of anti-cholesterol medicines in silencing Wnt signaling and perhaps inhibiting Wnt-driven cancers.
Tuesday, July 22, 2014
Friday, June 27, 2014
With the advent of microarray expression profiling over a decade ago, many new biomarkers have been identified for ER+ breast cancers, such as the transcription factors GATA-3 and XBP-1. A recent paper* identified a novel biomarker for triple-negative (ER- PR- HER2-) breast cancer. RUNX1 is a transcription factor that is the most frequently mutated gene in human leukemia, and the RUNX family plays essential roles in haematopoiesis, osteogenesis and neurogenesis.
In this report, the authors utilized a tissue microarray continaing biopsies from 483 patients with invasive ductal breast adenocarcinoma. The microarray was stained with antibodies for immunihistochemistry. RUNX1 immunostaining was signficantly asociated with pooere cancer-specific survival in patients with ER-negative and triple-negative breast cancer. However, RUNX1 was associated with progesterone receptor positive tumors as well, which is a bit confounding. Interestinlgly, RUNX1 was associated with more CD4+ and CD8+ T-lymphocyte infiltration and CD68+ macrophage infiltration, which have been observed as markers for poor prognosis in breast cancer patients.
Triple negative breast cancer is an unmet medical need and lacks suitable biomarkers for patient stratification. RUNX1 may be used as a biomarker and prognostic indicator correlating with poor prognosis specifically in the triple negative subtype of human breast cancer.