- Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers BREAST CANCER RESEARCH 2016; 18
Chemoradiotherapy for squamous cell carcinoma of the anal canal: Comparison of one versus two cycles mitomycin-C
RADIOTHERAPY AND ONCOLOGY
2015; 117 (2): 240-245
Concurrent chemoradiotherapy with 5-fluorouracil (5-FU) and mitomycin-C (MMC) is standard treatment for anal cancer. Randomized clinical trials in Europe have used 1 cycle MMC, while North American studies use 2 cycles. We compared treatment outcomes between patients treated with either 1 or 2 cycles of concurrent MMC.217 consecutive patients were treated definitively with chemoradiation from 2004 to 2012 in an integrated health system. Concurrent chemotherapy regimen depended on individual practice, and consisted of 2 cycles 5-FU (1000 mg/m(2)/day on days 1-4 and 29-32), along with MMC (10-15 mg/m(2)), given on either day 1 alone (n = 154), or days 1 and 29 (n = 63). Outcomes included progression-free (PFS), cancer-specific (CSS), overall (OS), and colostomy-free survival (CFS), as well as toxicity criteria.Median age 60 years, 70% female, 52% T3-T4, and 40% node-positive. Median follow-up 26 months. At 2 years, outcomes were: PFS 80%, CSS 89%, OS 86%, and CFS 88%. There was no difference in PFS (HR 0.85, 95% CI 0.37-1.92), CSS (HR 0.32, 95% CI 0.07-1.42), OS (HR 0.67, 95% CI 0.25-1.83), or CFS (HR 0.91, 95% CI 0.31-2.67) between the MMC1 and MMC2 groups. Stage and male gender were predictive of worse outcomes. Acute grade ⩾ 2 toxicities were worse in the MMC2 group. There were 3 treatment-related deaths, all in the MMC2 group.This study suggests that MMC1 is efficacious and may be an alternative to MMC2 in patients with anal cancer treated with definitive chemoradiation, with the potential for less acute treatment-related toxicity. Randomized trials comparing these two regimens could be considered.
View details for DOI 10.1016/j.radonc.2015.08.015
View details for Web of Science ID 000370460400008
View details for PubMedID 26347494
Molecular Subtype and Response to Dasatinib, an Src/Abl Small Molecule Kinase Inhibitor, in Hepatocellular Carcinoma Cell Lines In Vitro
2013; 57 (5): 1838-1846
Hepatocellular carcinoma (HCC) is the fifth most common malignancy and is the third leading cause of cancer death worldwide. Recently, the multitargeted kinase inhibitor sorafenib was shown to be the first systemic agent to improve survival in advanced HCC. Unlike other malignancies such as breast cancer, in which molecular subtypes have been clearly defined (i.e., luminal, HER2 amplified, basal, etc.) and tied to effective molecular therapeutics (hormone blockade and trastuzumab, respectively), in HCC this translational link does not exist. Molecular profiling studies of human HCC have identified unique molecular subtypes of the disease. We hypothesized that a panel of human HCC cell lines would maintain molecular characteristics of the clinical disease and could then be used as a model for novel therapeutics. Twenty human HCC cell lines were collected and RNA was analyzed using the Agilent microarray platform. Profiles from the cell lines in vitro recapitulate previously described subgroups from clinical material. Next, we evaluated whether molecular subgroup would have predictive value for response to the Src/Abl inhibitor dasatinib. The results demonstrate that sensitivity to dasatinib was associated with a progenitor subtype. Dasatinib was effective at inducing cell cycle arrest and apoptosis in "progenitor-like" cell lines but not in resistant lines.These findings suggest that cell line models maintain the molecular background of HCC and that subtype may be important for selecting patients for response to novel therapies. In addition, it highlights a potential role for Src family signaling in this progenitor subtype of HCC.
View details for DOI 10.1002/hep.26223
View details for Web of Science ID 000318162200020
View details for PubMedID 23299860
Recombination-Associated Sequence Homogenization of Neighboring Alu Elements: Signature of Nonallelic Gene Conversion
MOLECULAR BIOLOGY AND EVOLUTION
2010; 27 (10): 2300-2311
Recently, researchers have begun to recognize that, in order to establish neutral models for disease association and evolutionary genomics studies, it is crucial to have a clear understanding of the genomic impact of nonallelic gene conversion. Drawing on previous successes in characterizing this phenomenon over protein-coding gene families, we undertook a computational analysis of neighboring Alu sequences in the genome scale. For this purpose, we developed adjusted comutation rate (aCMR), a novel statistical method measuring the excess number of identical point mutations shared by adjacent Alu sequences, vis-à-vis random pairs. Using aCMR, we uncovered a remarkable genome-wide sequence homogenization of neighboring Alus, with the strongest signal observed in the pseudoautosomal regions of the X and Y chromosomes. The magnitude of sequence homogenization between Alu pairs is greater with shorter interlocus distance, higher sequence identity, and parallel orientation. Moreover, shared substitutions show a strong directionality toward GC nucleotides, with multiple substitutions tending to cluster within the Alu sequence. Taken together, these observed recombination-associated sequence homogenization patterns are best explained by frequent ubiquitous gene conversion events between neighboring Alus. We believe that these observations help to illuminate the nature and impact of the enigmatic phenomenon of gene conversion.
View details for DOI 10.1093/molbev/msq116
View details for Web of Science ID 000282174600010
View details for PubMedID 20453015
SRC: A Century of Science Brought to the Clinic
2010; 12 (8): 599-607
The SRC family kinases are the largest family of nonreceptor tyrosine kinases and one of the best-studied targets for cancer therapy. SRC, arguably the oldest oncogene, has been implicated in pathways regulating proliferation, angiogenesis, invasion and metastasis, and bone metabolism. More recently, researchers have proposed that the transforming ability of SRC is linked to its ability to activate key signaling molecules in these pathways, rather than through direct activity. It has been hypothesized that blocking SRC activation may inhibit these pathways, resulting in antitumor activity. However, successfully targeting SRC in a clinical setting remains a challenge, and SRC inhibitors have only recently begun to move through clinical development. Preclinical studies have identified specific molecular "subgroups" and histologies that may be more sensitive to SRC inhibition. In addition, other studies have demonstrated synergistic interactions between SRC inhibitors and other targeted therapies and cytotoxics. In this review, we summarize SRC biology and how it has been applied to the clinical development of SRC inhibitors. The status of SRC inhibitors, including dasatinib, saracatinib, and bosutinib, which are in phase 1, 2, and 3 trials, is highlighted.
View details for DOI 10.1593/neo.10328
View details for Web of Science ID 000280613500001
View details for PubMedID 20689754