Harnessing transcriptional regulation of alternative end-joining to predict cancer treatment.

Alternative end-joining (alt-EJ) is an error-prone DNA repair pathway that cancer cells deficient in homologous recombination rely on, making them vulnerable to synthetic lethality via inhibition of poly(ADP-ribose) polymerase (PARP). Targeting alt-EJ effector DNA polymerase theta (POLθ), which synergizes with PARP inhibitors and can overcome resistance, is of significant preclinical and clinical interest. However, the transcriptional regulation of alt-EJ and its interactions with processes driving cancer progression remain poorly understood.

Identification of differential biological activity and synergy between the PARP inhibitor rucaparib and its major metabolite.

The (poly)pharmacology of drug metabolites is seldom comprehensively characterized in drug discovery. However, some drug metabolites can reach high plasma concentrations and display in vivo activity. Here, we use computational and experimental methods to comprehensively characterize the kinase polypharmacology of M324, the major metabolite of the PARP1 inhibitor rucaparib.

Chemotherapy in metastatic castration-resistant prostate cancer: Current scenario and future perspectives.

Taxanes - docetaxel and cabazitaxel - are the most active chemotherapy drugs currently used for the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, despite a good initial response and survival benefit, nearly all patients eventually develop resistance, which is an important barrier to long-term survival. Resistance to taxanes is also associated with cross-resistance to androgen receptor signaling inhibitors (ARSIs).

Loss of TGFβ signaling increases alternative end-joining DNA repair that sensitizes to genotoxic therapies across cancer types.

Among the pleotropic roles of transforming growth factor-β (TGFβ) signaling in cancer, its impact on genomic stability is least understood. Inhibition of TGFβ signaling increases use of alternative end joining (alt-EJ), an error-prone DNA repair process that typically functions as a "backup" pathway if double-strand break repair by homologous recombination or nonhomologous end joining is compromised. However, the consequences of this functional relationship on therapeutic vulnerability in human cancer remain unknown.

A modular master regulator landscape controls cancer transcriptional identity.

Despite considerable efforts, the mechanisms linking genomic alterations to the transcriptional identity of cancer cells remain elusive. Integrative genomic analysis, using a network-based approach, identified 407 master regulator (MR) proteins responsible for canalizing the genetics of individual samples from 20 cohorts in The Cancer Genome Atlas (TCGA) into 112 transcriptionally distinct tumor subtypes. MR proteins could be further organized into 24 pan-cancer, master regulator block modules (MRBs), each regulating key cancer hallmarks and predictive of patient outcome in multiple cohorts.

Taxane-induced Attenuation of the CXCR2/BCL-2 Axis Sensitizes Prostate Cancer to Platinum-based Treatment.

Background: Taxanes are the most active chemotherapy agents in metastatic castration-resistant prostate cancer (mCRPC) patients; yet, resistance occurs almost invariably, representing an important clinical challenge. Taxane-platinum combinations have shown clinical benefit in a subset of patients, but the mechanistic basis and biomarkers remain elusive.

Objective: To identify mechanisms and response indicators for the antitumor efficacy of taxane-platinum combinations in mCRPC.

Sensitivity of cervico-vaginal cytology in endometrial carcinoma: A systematic review and meta-analysis.

Cervico-vaginal cytology is primarily a cervical cancer screening test. The anatomical continuity of the uterine cavity with the cervix makes the Papanicolaou (Pap) test accessible to evaluate signs of disease shed from the endometrium. Our aim was to determine the sensitivity of routine Pap test in endometrial carcinoma detection and its relationship with clinico-pathologic factors.

Defining a mutational signature for endometrial cancer screening and early detection.

Introduction: The current availability of genomic information represents an opportunity to develop new strategies for early detection of cancer. New molecular tests for endometrial cancer may improve performance and failure rates of histological aspirate-based diagnosis, and provide promising perspectives for a potential screening scenario. However, the selection of relevant biomarkers to develop efficient strategies can be a challenge.

New perspectives on screening and early detection of endometrial cancer.

Due to the anatomical continuity of the uterine cavity with the cervix, genomic exploitation of material from routine Pap smears and other noninvasive sampling methods represent a unique opportunity to detect signs of disease using biological material shed from the upper genital tract. Recent research findings offer a promising perspective in the detection of endometrial cancer, but certain questions need to be addressed in order to accelerate the implementation of novel technologies in a routine screening or clinical setting. We discuss here new perspectives on detection of endometrial cancer using genomic and other biomarkers in minimally invasive sampling methods with a special focus on public health classic screening criteria, highlighting current gaps in knowledge.

BRCA2 and Other DDR Genes in Prostate Cancer.

Germline and somatic aberrations in DNA damage repair (DDR) genes are more prevalent in prostate cancer than previously recognized, with as the most commonly altered gene. Germline mutations in have been linked to poor prognosis when patients are managed under the protocols currently approved for prostate cancer. The impact of germline mutations in other DDR genes beyond remain unclear.

NSD2 is a conserved driver of metastatic prostate cancer progression.

Deciphering cell-intrinsic mechanisms of metastasis progression in vivo is essential to identify novel therapeutic approaches. Here we elucidate cell-intrinsic drivers of metastatic prostate cancer progression through analyses of genetically engineered mouse models (GEMM) and correlative studies of human prostate cancer. Expression profiling of lineage-marked cells from mouse primary tumors and metastases defines a signature of de novo metastatic progression.

Epigenetic Regulation in Prostate Cancer Progression.

Purpose Of Review: An important number of newly identified molecular alterations in prostate cancer affect gene encoding master regulators of chromatin biology epigenetic regulation. This review will provide an updated view of the key epigenetic mechanisms underlying prostate cancer progression, therapy resistance, and potential actionable mechanisms and biomarkers.

Recent Findings: Key players in chromatin biology and epigenetic master regulators has been recently described to be crucially altered in metastatic CRPC and tumors that progress to AR independency.

Predicting Drug Response in Human Prostate Cancer from Preclinical Analysis of In Vivo Mouse Models.

Although genetically engineered mouse (GEM) models are often used to evaluate cancer therapies, extrapolation of such preclinical data to human cancer can be challenging. Here, we introduce an approach that uses drug perturbation data from GEM models to predict drug efficacy in human cancer. Network-based analysis of expression profiles from in vivo treatment of GEM models identified drugs and drug combinations that inhibit the activity of FOXM1 and CENPF, which are master regulators of prostate cancer malignancy.

Characterization of an acromesomelic dysplasia, Grebe type case: novel mutation affecting the recognition motif at the processing site of GDF5.

Acromesomelic dysplasia, Grebe type is a very rare skeletal dysplasia characterized by severe dwarfism with marked micromelia and deformation of the upper and lower limbs, with a proximodistal gradient of severity. CDMP1 gene mutations have been associated with Grebe syndrome, Hunter-Thompson syndrome, Du Pan syndrome and brachydactyly type C. The proband is a 4-year-old boy, born of consanguineous Pakistani parents.

DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis.

Emerging evidence demonstrates that the DNA repair kinase DNA-PKcs exerts divergent roles in transcriptional regulation of unsolved consequence. Here, in vitro and in vivo interrogation demonstrate that DNA-PKcs functions as a selective modulator of transcriptional networks that induce cell migration, invasion, and metastasis. Accordingly, suppression of DNA-PKcs inhibits tumor metastases.

Cross-species regulatory network analysis identifies a synergistic interaction between FOXM1 and CENPF that drives prostate cancer malignancy.

To identify regulatory drivers of prostate cancer malignancy, we have assembled genome-wide regulatory networks (interactomes) for human and mouse prostate cancer from expression profiles of human tumors and of genetically engineered mouse models, respectively. Cross-species computational analysis of these interactomes has identified FOXM1 and CENPF as synergistic master regulators of prostate cancer malignancy. Experimental validation shows that FOXM1 and CENPF function synergistically to promote tumor growth by coordinated regulation of target gene expression and activation of key signaling pathways associated with prostate cancer malignancy.

A molecular signature predictive of indolent prostate cancer.

Many newly diagnosed prostate cancers present as low Gleason score tumors that require no treatment intervention. Distinguishing the many indolent tumors from the minority of lethal ones remains a major clinical challenge. We now show that low Gleason score prostate tumors can be distinguished as indolent and aggressive subgroups on the basis of their expression of genes associated with aging and senescence.

ETV4 promotes metastasis in response to activation of PI3-kinase and Ras signaling in a mouse model of advanced prostate cancer.

Combinatorial activation of PI3-kinase and RAS signaling occurs frequently in advanced prostate cancer and is associated with adverse patient outcome. We now report that the oncogenic Ets variant 4 (Etv4) promotes prostate cancer metastasis in response to coactivation of PI3-kinase and Ras signaling pathways in a genetically engineered mouse model of highly penetrant, metastatic prostate cancer. Using an inducible Cre driver to simultaneously inactivate Pten while activating oncogenic Kras and a fluorescent reporter allele in the prostate epithelium, we performed lineage tracing in vivo to define the temporal and spatial occurrence of prostate tumors, disseminated tumor cells, and metastases.

B-Raf activation cooperates with PTEN loss to drive c-Myc expression in advanced prostate cancer.

Both the PI3K → Akt → mTOR and mitogen-activated protein kinase (MAPK) signaling pathways are often deregulated in prostate tumors with poor prognosis. Here we describe a new genetically engineered mouse model of prostate cancer in which PI3K-Akt-mTOR signaling is activated by inducible disruption of PTEN, and extracellular signal-regulated kinase 1/2 (ERK1/2) MAPK signaling is activated by inducible expression of a BRAF(V600E) oncogene. These tissue-specific compound mutant mice develop lethal prostate tumors that are inherently resistant to castration.

Dual targeting of the Akt/mTOR signaling pathway inhibits castration-resistant prostate cancer in a genetically engineered mouse model.

Although the prognosis for clinically localized prostate cancer is now favorable, there are still no curative treatments for castration-resistant prostate cancer (CRPC) and, therefore, it remains fatal. In this study, we investigate a new therapeutic approach for treatment of CRPC, which involves dual targeting of a major signaling pathway that is frequently deregulated in the disease. We found that dual targeting of the Akt and mTOR signaling pathways with their respective inhibitors, MK-2206 and ridaforolimus (MK-8669), is highly effective for inhibiting CRPC in preclinical studies in vivo using a refined genetically engineered mouse model of the disease.

Stromal interaction molecule 2 (STIM2) is frequently overexpressed in colorectal tumors and confers a tumor cell growth suppressor phenotype.

Allelic imbalances at chromosome 4p have been largely documented in many different tumor types. In colorectal cancer, loss of heterozygosity (LOH) at 4p15 has been associated with tumor aggressiveness and poor patient outcome, however no target genes in the region have been identified to date. Since stromal interaction molecule 2 (STIM2) is located at 4p15.