17 research outputs found
Hypertonicity counteracts MCL 1 and renders BCL XL a synthetic lethal target in head and neck cancer
Head and neck squamous cell carcinoma (HNSCC) is an aggressive and difficultâtoâtreat cancer entity. Current therapies ultimately aim to activate the mitochondriaâcontrolled (intrinsic) apoptosis pathway, but complex alterations in intracellular signaling cascades and the extracellular microenvironment hamper treatment response. On the one hand, proteins of the BCLâ2 family set the threshold for cell death induction and prevent accidental cellular suicide. On the other hand, controlling a cell's readiness to die also determines whether malignant cells are sensitive or resistant to anticancer treatments. Here, we show that HNSCC cells upregulate the proapoptotic BH3âonly protein NOXA in response to hyperosmotic stress. Induction of NOXA is sufficient to counteract the antiapoptotic properties of MCLâ1 and switches HNSCC cells from dual BCLâXL/MCLâ1 protection to exclusive BCLâXL addiction. Hypertonicityâinduced functional loss of MCLâ1 renders BCLâXL a synthetically lethal target in HNSCC, and inhibition of BCLâXL efficiently kills HNSCC cells that poorly respond to conventional therapies. We identify hypertonicityâinduced upregulation of NOXA as link between osmotic pressure in the tumor environment and mitochondrial priming, which could perspectively be exploited to boost efficacy of anticancer drugs
Imaging response assessment for predicting outcomes after bioselection chemotherapy in larynx cancer: A secondary analysis of two prospective trials
Background and purpose: Bioselection with induction chemotherapy in larynx cancer is associated with excellent larynx preservation and disease-specific survival but requires visual inspection of the primary tumor. We retrospectively compare clinical and imaging response in bioselected patients to develop predictive models of surgeon-assessed response (SR), laryngectomy-free survival (LFS), and overall survival (OS) in bioselected patients. Materials and methods: In a secondary analysis of patients on two single-institution bioselection trials, model building used a regularized regression model (elastic-net) and applied nested cross-validation. Logistic regression-based model was used to predict SR and Cox proportional hazard-based models were used to predict LFS and OS. Results: In 115 patients with a median age of 57 years, most patients had supraglottic tumors (73.0%) and T3/T4 disease (94.8%). Definitive treatment was chemoradiation in 76.5% and laryngectomy in 23.5%. Change in primary tumor (OR = 5.78, p < 0.001) and N-classification (OR = 1.64, p = 0.003) predicted SR (AUC 0.847). Change in tumor volume (HR = 0.58, p < 0.001) predicted LFS (c-index 0.724). N-classification (HR = 1.48, p = 0.04) and pre-chemotherapy tumor volume (HR = 1.30, p = 0.174) predicted OS (c-index 0.552). Conclusions: Imaging offers a non-invasive opportunity to evaluate response to induction chemotherapy, complementary to surgeon assessment. Further evaluation of approaches to bioselection that optimize generalizability of this paradigm are needed, and clinical trials utilizing imaging to predict outcomes including LFS are warranted.http://deepblue.lib.umich.edu/bitstream/2027.42/191971/2/Imaging response assessment for predicting outcomes after bioselection chemotherapy in larynx cancer A secondary analysis of.pdfPublished versionDescription of Imaging response assessment for predicting outcomes after bioselection chemotherapy in larynx cancer A secondary analysis of.pdf : Published versio
Clinical characteristics and prognosis of Chinese patients with hereditary transthyretin amyloid cardiomyopathy
Pharmacokinetics of Patisiran, the First Approved RNA Interference Therapy in Patients With Hereditary TransthyretinâMediated Amyloidosis
Impact of Delayed Diagnosis and Misdiagnosis for Patients with Transthyretin Amyloid Cardiomyopathy (ATTR-CM): A Targeted Literature Review
A phase II trial of the BCL-2 homolog domain 3 mimetic AT-101 in combination with docetaxel for recurrent, locally advanced, or metastatic head and neck cancer
Cervical metastasis of gingival carcinoma misdiagnosed as branchiogenic carcinoma, a rare entity - report of a case and review of literature
BH3 mimetic-elicited Ca2+ signals in pancreatic acinar cells are dependent on Bax and can be reduced by Ca2+-like peptides
BH3 mimetics are small-molecule inhibitors of B-cell lymphoma-2 (Bcl-2) and Bcl-xL, which disrupt the heterodimerisation of anti- and pro-apoptotic Bcl-2 family members sensitising cells to apoptotic death. These compounds have been developed as anti-cancer agents to counteract increased levels of Bcl-2 proteins often present in cancer cells. Application of a chemotherapeutic drug supported with a BH3 mimetic has the potential to overcome drug resistance in cancers overexpressing anti-apoptotic Bcl-2 proteins and thus increase the success rate of the treatment. We have previously shown that the BH3 mimetics, BH3I-2âČ and HA14-1, induce Ca2+ release from intracellular stores followed by a sustained elevation of the cytosolic Ca2+ concentration. Here we demonstrate that loss of Bax, but not Bcl-2 or Bak, inhibits this sustained Ca2+ elevation. What is more, in the absence of Bax, thapsigargin-elicited responses were decreased; and in two-photon-permeabilised baxâ/â cells, Ca2+ loss from the ER was reduced compared to WT cells. The Ca2+-like peptides, CALP-1 and CALP-3, which activate EF hand motifs of Ca2+-binding proteins, significantly reduced excessive Ca2+ signals and necrosis caused by two BH3 mimetics: BH3I-2âČ and gossypol. In the presence of CALP-1, cell death was shifted from necrotic towards apoptotic, whereas CALP-3 increased the proportion of live cells. Importantly, neither of the CALPs markedly affected physiological Ca2+ signals elicited by ACh, or cholecystokinin. In conclusion, the reduction in passive ER Ca2+ leak in baxâ/â cells as well as the fact that BH3 mimetics trigger substantial Ca2+ signals by liberating Bax, indicate that Bax may regulate Ca2+ leak channels in the ER. This study also demonstrates proof-of-principle that pre-activation of EF hand Ca2+-binding sites by CALPs can be used to ameliorate excessive Ca2+ signals caused by BH3 mimetics and shift necrotic death towards apoptosis