NVP-BYL719 PI3Kα Inhibitor and Predictive Modeling of Response
Novel targeted therapeutics, designed to modulate aberrant functions elicited by cancer-specific genetic alterations upon which the disease depends, require well-defined patient stratification strategies in order to maximize their therapeutic impact and benefit for the patients. Here, Fritsch and colleagues describe the application of the Cancer Cell Line Encyclopedia as a preclinical platform to refine the patient stratification strategy for NVP-BYL719, a novel, potent, and selective PI3Kα-specific inhibitor currently in clinical development. The authors found that PIK3CA mutation was the foremost positive predictor of sensitivity while revealing additional positive and negative associations such as PIK3CA amplification and PTEN mutation, respectively.
Regulation of STAT5 Function by BRD2 in Leukemias
It is known that the transcription factor STAT5 is a potential therapeutic target for hematological malignancies. Bromodomain-containing proteins play an important role in transcriptional regulation. In this study, Liu and colleagues analyzed the interaction between STAT5 and bromodomain-containing proteins and found that the bromodomain family protein BRD2 is an important cofactor for STAT5 transcriptional function. Furthermore, inhibition of BRD2, particularly in combination with specific kinase inhibitors, can induce apoptosis in leukemia cell lines and primary leukemia cells dependent on STAT5, but not in normal hematopoietic cells. These findings suggest a novel rational strategy for treating leukemias and lymphomas driven by constitutive STAT5 activation.
JAK1/JAK2 Inhibition Suppresses Prostate Cancer Metastases
Metastatic prostate cancer is lethal and lacks effective strategies for prevention or treatment, requiring novel therapeutic approaches. Interleukin-6 (IL-6) is a multifunctional cytokine implicated in prostate cancer pathogenesis. In this study, Gu and colleagues investigated the direct functional role of IL-6 in metastatic progression of prostate cancer. IL-6 promoted prostate cancer metastases in vitro and in vivo via Jak2-Stat3 signaling pathway. IL-6–driven metastasis was effectively suppressed by pharmacological targeting of Jak1/2 by Jak1/2 inhibitor AZD1480. Pharmacological Jak1/2 inhibition may provide a novel treatment strategy for advanced prostate cancer.
GALR2-Induced p38 MAPK Promotes Cytokine Secretion and Tumor Angiogenesis
Cancer therapeutics targeting individual cytokines are ineffective in improving patient survival likely due to overlapping effects between multiple cytokines. Here, Banerjee, Van Tubergen, and colleagues describe a novel angiogenic signaling cascade in squamous cell carcinoma of the head and neck (SCCHN), driven by GALR2, a G protein–coupled receptor. GALR2 promotes p38-MAPK and down-regulates the RNA-degrading protein tristetraprolin, leading to enhanced secretion of proangiogenic cytokines and angiogenesis. Targeting upstream regulators of angiogenesis may be a more effective clinical strategy than modulation of individual cytokines. Therefore, this study indicated that GALR2/p38-mediated cytokine secretion may be an excellent target for new adjuvant therapy in SCCHN.
- ©2014 American Association for Cancer Research.