Mutant IDH1 Downregulates ATM and Alters DNA Repair and Sensitivity to DNA Damage Independent of TET2.
Cancer Cell 30(2):337 (2016)
Mutations in the isocitrate dehydrogenase-1 gene (IDH1) are common drivers of acute myeloid leukemia (AML) but their mechanism is not fully understood. It is thought that IDH1 mutants act by inhibiting TET2 to alter DNA methylation, but there are significant unexplained clinical differences betw...
A phase I trial of ANG1/2-Tie2 inhibitor trebaninib (AMG386) and temsirolimus in advanced solid tumors (PJC008/NCI♯9041).
Investigational New Drugs 34(1):104 (2016)
There is crosstalk between the ANG-Tie2 and the PI3K/Akt/mTOR pathways. Combined ANG1/2 and mTOR blockade may have additive anti-cancer activity. The combination of trebananib, an inhibitor of ANG1/2-Tie2 interaction, with temsirolimus was evaluated in patients with advanced solid tumors to dete...
NRF2 Pathway Activation and Adjuvant Chemotherapy Benefit in Lung Squamous Cell Carcinoma.
Clinical Cancer Research 21(11):2499 (2015)
Genomic profiling of lung squamous cell carcinomas (SCC) has identified NRF2 pathway alterations, which activate oxidative response pathways, in one third of tumors. Preclinical data suggest these tumors may be resistant to platinum-based chemotherapy. We evaluated the clinical relevance of thes...
PIK3CA genotype and treatment decisions in human epidermal growth factor receptor 2-positive breast cancer.
Journal of Clinical Oncology 33(12):1318 (2015)
APOBEC3B expression in breast cancer reflects cellular proliferation, while a deletion polymorphism is associated with immune activation.
PNAS 112(9):2841 (2015)
Genomic sequencing studies of breast and other cancers have identified patterns of mutations that have been attributed to the endogenous mutator activity of APOBEC3B (A3B), a member of the AID/APOBEC family of cytidine deaminases. A3B gene expression is increased in many cancers, but its upstrea...
Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression.
Cancer Cell 27(2):211 (2015)
Controversy over the role of antioxidants in cancer has persisted for decades. Here, we demonstrate that synthesis of the antioxidant glutathione (GSH), driven by GCLM, is required for cancer initiation. Genetic loss of Gclm prevents a tumor's ability to drive malignant transformation. Intriguin...
Breaking up is hard to do: PI3K isoforms on the rebound.
Cancer Cell 27(1):5 (2015)
In this issue of Cancer Cell, Schwartz and colleagues and Costa and colleagues demonstrate that inhibition of PI3Kα or PI3Kβ in cancer cells with hyperactivated PI3Kα or PI3Kβ, respectively, activates the other isoform, leading to a "rebound" of the PI3K activity through different compensation m...
Functional characterization of CFI-400945, a Polo-like kinase 4 inhibitor, as a potential anticancer agent.
Cancer Cell 26(2):163 (2014)
PLK4 was identified as a promising therapeutic target through a systematic approach that combined RNAi screening with gene expression analysis in human breast cancers and cell lines. A drug discovery program culminated in CFI-400945, a potent and selective PLK4 inhibitor. Cancer cells treated wi...
Estrogen controls the survival of BRCA1-deficient cells via a PI3K-NRF2-regulated pathway.
PNAS 111(12):4472 (2014)
Mutations in the tumor suppressor BRCA1 predispose women to breast and ovarian cancers. The mechanism underlying the tissue-specific nature of BRCA1's tumor suppression is obscure. We previously showed that the antioxidant pathway regulated by the transcription factor NRF2 is defective in BRCA1-...
Extended adjuvant tamoxifen for early breast cancer: a meta-analysis.
PLoS ONE 9(2):e88238 (2014)
Hormone receptor positive breast cancer is characterized by the potential for disease recurrence many years after initial diagnosis. Endocrine therapy has been shown to reduce the risk of such recurrence, but the optimal duration of endocrine therapy remains unclear.
We conducted a systematic re...
BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival.
Journal of Experimental Medicine 210(8):1529 (2013)
Oxidative stress plays an important role in cancer development and treatment. Recent data implicate the tumor suppressor BRCA1 in regulating oxidative stress, but the molecular mechanism and the impact in BRCA1-associated tumorigenesis remain unclear. Here, we show that BRCA1 regulates Nrf2-depe...
Feasibility of a randomized controlled trial of vitamin D vs. placebo in women with recently diagnosed breast cancer.
Breast Cancer Research and Treatment 134(2):759 (2012)
Low serum vitamin D levels have been associated with poor outcomes in women diagnosed with early breast cancer. However, no randomized controlled trials (RCTs) have been performed to determine whether vitamin D supplementation might be an effective intervention in this population. We prospective...
Pharmacogenetic and germline prognostic markers of lung cancer.
Journal of Thoracic Oncology 6(2):296 (2011)
Lung cancer is the leading global cause of cancer-related mortality. Interindividual variability in treatment response and cancer outcomes has focused attention on genetic polymorphisms as prognostic markers. We evaluated the overall contribution of candidate polymorphism association studies to ...
Presentation of nonfinal results of randomized controlled trials at major oncology meetings.
Journal of Clinical Oncology 27(24):3938 (2009)
To assess the frequency, implications, and factors associated with reporting nonfinal analyses (NFAs) of randomized controlled trials (RCTs) as abstract publications.
We identified 138 consecutive reports of RCTs testing systemic therapy for lymphoma, breast, colorectal, or non-small-cell lung c...
p53 Arg72Pro and MDM2 T309G polymorphisms, histology, and esophageal cancer prognosis.
Clinical Cancer Research 15(9):3103 (2009)
This study aimed to evaluate the prognostic significance of two functional single nucleotide polymorphisms (SNP) in the p53 pathway (p53 Arg72Pro and MDM2 T309G) in patients with esophageal cancer, and to determine the importance of histologic subtype in the SNP-outcome relationships.
A cohort o...
Discoloration of skin and urine after treatment with hydroxocobalamin for cyanide poisoning.
Canadian Medical Association Journal 180(2):251 (2009)
Evolution of the randomized controlled trial in oncology over three decades.
Journal of Clinical Oncology 26(33):5458 (2008)
The randomized controlled trial (RCT) is the gold standard for establishing new therapies in clinical oncology. Here we document changes with time in design, sponsorship, and outcomes of oncology RCTs.
Reports of RCTs evaluating systemic therapy for breast, colorectal (CRC), and non-small-cell l...
Bowel loops and eyelid droops.
Canadian Medical Association Journal 179(9):927 (2008)
A patient presented with a small-bowel obstruction associated with signs and symptoms of botulism. Fecal cultures were positive for viable Clostridium botulinum. This case emphasizes the importance of a broad differential diagnosis and doing a complete examination to account for all signs and sy...
Barcoded medication administration: a last line of defense.
JAMA 299(18):2200 (2008)
Invasive pulmonary aspergillosis associated with marijuana use in a man with colorectal cancer.
Journal of Clinical Oncology 26(13):2214 (2008)