Systemic Therapy for Hereditary Breast Cancers.

Approximately 5% to 10% of all breast cancers are hereditary; many of which are caused by pathogenic variants in genes required for homologous recombination, including BRCA1 and BRCA2. Here we discuss systemic treatment for such breast cancers, including approved chemotherapeutic approaches and also targeted treatment approaches using poly-(ADP ribose) polymerase inhibitors. We also discuss experimental approaches to treating hereditary breast cancer, including new small molecule DNA repair inhibitors and also immunomodulatory agents. Finally, we discuss how drug resistance emerges in patients with hereditary breast cancer, how this might be delayed or prevented, and how biomarker-adapted treatment is molding the future management of hereditary breast cancer

Translational genomics of ovarian clear cell carcinoma.

Ovarian clear cell carcinomas (OCCC) are rare aggressive, chemo-resistant tumours comprising approximately 13% of all epithelial ovarian cancers, which have distinct clinical and molecular features, when compared to other gynaecological malignancies. At present, there are no specific licensed targeted therapies for OCCC, although a number of candidate targets have been identified. This review focuses on recent knowledge underpinning our understanding of the pathogenesis of OCCC including direct and synthetic-lethal therapeutic strategies in particular focussing on ARID1A deficiency. We also discuss current targeted clinical trials and immunotherapeutic approaches

DAISY: picking synthetic lethals from cancer genomes.

A better understanding of genetic interactions in cancer might help identify new therapeutic approaches that exploit the concept of synthetic lethality. Ruppin and colleagues have developed a new computational method, DAISY, that predicts such interactions and potentially facilitates the delineation and validation of comprehensive genetic interaction networks

Synthetic Lethality and Cancer - Penetrance as the Major Barrier.

Synthetic lethality has long been proposed as an approach for targeting genetic defects in tumours. Despite a decade of screening efforts, relatively few robust synthetic lethal targets have been identified. Improved genetic perturbation techniques, including CRISPR/Cas9 gene editing, have resulted in renewed enthusiasm for searching for synthetic lethal effects in cancer. An implicit assumption behind this enthusiasm is that the lack of reproducibly identified targets can be attributed to limitations of RNAi technologies. We argue here that a bigger hurdle is that most synthetic lethal interactions (SLIs) are not highly penetrant, in other words they are not robust to the extensive molecular heterogeneity seen in tumours. We outline strategies for identifying and prioritising SLIs that are most likely to be highly penetrant

An RNA interference screen for identifying downstream effectors of the p53 and pRB tumour suppressor pathways involved in senescence

Background: Cellular senescence is an irreversible cell cycle arrest that normal cells undergo in response to progressive shortening of telomeres, changes in telomeric structure, oncogene activation or oxidative stress and acts as an important tumour suppressor mechanism.Results: To identify the downstream effectors of the p53-p21 and p16-pRB tumour suppressor pathways crucial for mediating entry into senescence, we have carried out a loss-of-function RNA interference screen in conditionally immortalised human fibroblasts that can be induced to rapidly undergo senescence, whereas in primary cultures senescence is stochastic and occurs asynchronously. These cells are immortal but undergo a rapid irreversible arrest upon activation of the p53-p21 and p16-pRB pathways that can be readily bypassed upon their inactivation. The primary screen identified 112 known genes including p53 and another 29 shRNAmirs targetting as yet unidentified loci. Comparison of these known targets with genes known to be up-regulated upon senescence in these cells, by micro-array expression profiling, identified 4 common genes TMEM9B, ATXN10, LAYN and LTBP2/3. Direct silencing of these common genes, using lentiviral shRNAmirs, bypassed senescence in the conditionally immortalised cells.Conclusion: The senescence bypass screen identified TMEM9B, ATXN10, LAYN and LTBP2/3 as novel downstream effectors of the p53-p21 and p16-pRB tumour suppressor pathways. Although none of them has previously been linked to cellular senescence, TMEM9B has been suggested to be an upstream activator of NF-kappa B signalling which has been found to have a causal role in promoting senescence. Future studies will focus on determining on how many of the other primary hits also have a casual role in senescence and what is the mechanism of action

CancerGD: A Resource for Identifying and Interpreting Genetic Dependencies in Cancer.

Genes whose function is selectively essential in the presence of cancer-associated genetic aberrations represent promising targets for the development of precision therapeutics. Here, we present CancerGD, a resource that integrates genotypic profiling with large-scale loss-of-function genetic screens in tumor cell lines to identify such genetic dependencies. CancerGD provides tools for searching, visualizing, and interpreting these genetic dependencies through the integration of functional interaction networks. CancerGD includes different screen types (siRNA, shRNA, CRISPR), and we describe a simple format for submitting new datasets

PARP inhibitor combination therapy.

In 2014, olaparib (Lynparza) became the first PARP (Poly(ADP-ribose) polymerase) inhibitor to be approved for the treatment of cancer. When used as single agents, PARP inhibitors can selectively target tumour cells with BRCA1 or BRCA2 tumour suppressor gene mutations through synthetic lethality. However, PARP inhibition also shows considerable promise when used together with other therapeutic agents. Here, we summarise both the pre-clinical and clinical evidence for the utility of such combinations and discuss the future prospects and challenges for PARP inhibitor combinatorial therapies

Driver Oncogenes but Not as We Know Them: Targetable Fusion Genes in Breast Cancer.

Two reports in this issue of Cancer Discovery outline how the genomic composition of tumors, including the presence of intragenic gene fusions, could inform the selection of treatment approaches in aggressive forms of the disease. Cancer Discov; 8(3); 272-5. ©2018 AACRSee related article by Matissek et al., p. 336See related article by Liu et al., p. 354

A Compendium of Co-regulated Protein Complexes in Breast Cancer Reveals Collateral Loss Events.

Protein complexes are responsible for the bulk of activities within the cell, but how their behavior and abundance varies across tumors remains poorly understood. By combining proteomic profiles of breast tumors with a large-scale protein-protein interaction network, we have identified a set of 285 high-confidence protein complexes whose subunits have highly correlated protein abundance across tumor samples. We used this set to identify complexes that are reproducibly under- or overexpressed in specific breast cancer subtypes. We found that mutation or deletion of one subunit of a co-regulated complex was often associated with a collateral reduction in protein expression of additional complex members. This collateral loss phenomenon was typically evident from proteomic, but not transcriptomic, profiles, suggesting post-transcriptional control. Mutation of the tumor suppressor E-cadherin (CDH1) was associated with a collateral loss of members of the adherens junction complex, an effect we validated using an engineered model of E-cadherin loss