The present invention concerns enriched heterogeneous mammalian renal cell populations characterized by biomarkers, and methods of making and using the same.

The present disclosure provides compositions and methods for the treatment of subjects having a risk of invasive breast cancer. In some embodiments, these aspects allow for the pairing of the proper treatment option for the particular subject. In some embodiments, this allows for identifying subjects who, while at risk for invasive breast cancer, will not normally respond to radiation therapy, and can instead receive an alternative therapy, such as a HER2 antibody.

Heritable mutations in the BRCA1 and BRCA2 and other genes in the DNA double-strand break (DSB) repair pathway increase risk of breast, ovarian and other cancers. In response to DNA breaks, the proteins encoded by these genes bind to each other and are transported into the nucleus to form nuclear foci and initiate homologous recombination. Flow cytometry-based functional variant analyses (FVAs) were developed to determine whether variants in BRCA1 or other DSB repair genes disrupted the binding of BRCA1 to its protein partners, the phosphorylation of p53 or the transport of the BRCA1complex to the nucleus in response to DNA damage. Each of these assays distinguished high-risk BRCA1 mutations from low-risk BRCA1 controls. Mutations in other DSB repair pathway genes produced molecular phenocopies with these assays. FVA assays may represent an adjunct to sequencing for categorizing VUS or may represent a stand-alone measure for assessing breast cancer risk.

Bacterial systems for screening for small molecule agents are disclosed herein. Kits for carrying out the screening are also disclosed.

The invention provides SKP2 as a biomarker to predict effective treatment of cancer using an MDM2 antagonist. Identifying this biomarker in a cancer patient allows a determination to be made whether the patient's cancer is likely to be successfully treated using an MDM2 antagonist. Accordingly, the invention relates generally to a companion diagnostic for MDM2 antagonist therapy. The SKP2 biomarker may be measured directly, or indirectly by detection of a molecule that is functionally upstream or downstream of SKP2 and the level of which correlates with the level of the SKP2 biomarker, such as the detection of one or more SKP2 substrates.

The present disclosure provides compositions and methods for the treatment of subjects having a risk of invasive breast cancer. In some embodiments, these aspects allow for the pairing of the proper treatment option for the particular subject. In some embodiments, this allows for identifying subjects who, while at risk for invasive breast cancer, will not normally respond to radiation therapy, and can instead receive an alternative therapy, such as a HER2 antibody.

Provided herein are methods for identifying pairs of protein binding partners, mutations of which may inform the discovery of pharmaceutically useful small molecules. The methods disclosed herein may allow for the adaptation of the native protein degradation system to modulate specific disease targets at the protein level, in particular, for targets that have long been considered undruggable.

The present disclosure provides compositions and methods for the treatment of subjects having a risk of invasive breast cancer. In some embodiments, these aspects allow for the pairing of the proper treatment option for the particular subject. In some embodiments, this allows for identifying subjects who, while at risk for invasive breast cancer, will not normally respond to radiation therapy, and can instead receive an alternative therapy, such as a HER2 antibody.

The present disclosure provides methods to identify peptides and small molecule moieties that are able to functionally bridge an interaction between a target protein and an E3 ubiquitin ligase to mediate the degradation of the target protein. Some moieties can degrade specific target variants, but not others. The moieties create a neosubstrate for an E3 ligase of interest. The methods described enable generation of compounds able to selectively degrade specific targets within cells with implications for drug development for pathological conditions. The disclosure also describes the generation of modified peptides using post-translational modification enzymes, such as N-methyltransferases, prolyloligopeptidases, lactamases, hydroxylases, and dehydratases, along with methods of using the same.

The invention relates to the use of an anti-tumour vaccine composed of two peptides of nine amino acids—native cryptic TERT572 (RLFFYRKSV, SEQ ID No. 1), expressed by tumour cells, and the optimised variant thereof TERT572Y (YLFFYRKSV, SEQ ID No. 2), for the treatment of a tumour expressing telomerase reverse transcriptase (TERT), in an HLA-A*0201 patient with a normal gamma glutamine transferase (gGT) level and/or a normal lactate dehydrogenase (LDH) level.