Abstract: A modular bioreactor system is provided including a platform having a seat to receive a modular tissue chamber, and one or more platform interfacial members; and a releasable modular tissue chamber including a bottom surface, an open top, and sidewalls defining a well therein, the releasable modular tissue chamber configured to be received by the seat of the platform, the tissue chamber further including an interfacial member configured to releasably connect the modular tissue chamber to the platform, wherein a tissue chamber contains human bone marrow (engineered using iPS cell derived osteoblasts, osteoclasts, endothelial cells, supporting mesenchymal cells, and hematopoietic cells in bone matrix) infused by primary leukemia cells

Abstract: Disclosed herein is a method for treating a solid tumor in a subject that involves detecting in a tumor biopsy sample from the subject enrichment of a cancer associated fibroblast (CAF) subset disclosed herein and then treating the subject with an immunotherapy. Also discussed is a method for treating a solid tumor in a subject that involves isolating cancer associated fibroblasts (CAFs) from the subject, isolating and expanding the disclosed subset of CAFs, and administering the expanded CAF subset to the subject in combination with an immunotherapy.

Abstract: The method of generating multipotent stem cells is a method for producing and/or expanding multipotent stem cells by delivering at least one reprogramming protein into somatic cells. The at least one reprogramming protein includes a Master Regulator (MR) protein, which may be BAZ2B, ZBTB20, ZMAT1, CNOT8, KLF12, DMTF1, HBP1, or FLI1. The bromodomain protein BAZ2B, in particular, was identified by first generating bi-species heterokaryons by fusing Tcf7l1?/? murine embryonic stem cells (ESCs) with human B-cell lymphocytes. Reprogramming of the B-cell nuclei to a multipotent state was tracked by human mRNA transcript profiling at multiple timepoints. Interrogation of a human B-cell regulatory network with gene expression signatures collected from such reprogramming time series identified eight candidate Master Regulator proteins, which were validated in human cord blood-derived hematopoietic progenitor and lineage-committed cells.

Abstract: The method of generating multipotent stem cells is a method for producing and/or expanding multipotent stem cells by delivering at least one reprogramming protein into somatic cells. The at least one reprogramming protein includes a Master Regulator (MR) protein, which may be BAZ2B, ZBTB20, ZMAT1, CNOT8, KLF12, DMTF1, HBP1, or FLI1. The bromodomain protein BAZ2B, in particular, was identified by first generating bi-species heterokaryons by fusing Tcf7l1?/? murine embryonic stem cells (ESCs) with human B-cell lymphocytes. Reprogramming of the B-cell nuclei to a multipotent state was tracked by human mRNA transcript profiling at multiple timepoints. Interrogation of a human B-cell regulatory network with gene expression signatures collected from such reprogramming time series identified eight candidate Master Regulator proteins, which were validated in human cord blood-derived hematopoietic progenitor and lineage-committed cells.

Abstract: Described herein is a therapeutic method that specifically addresses tumor-infiltrated regulatory T cells (Tregs) with minimal impact on the peripheral Tregs.

Abstract: Disclosed are systems and methods for culturing systemic bioengineered tumor models, including osteosarcoma cells or breast adenocarcinoma cells derived from patients. The model includes the tumor cells on host tissues such as bone, liver, lung, and heart tissue, wherein the bone, liver, lung, and heart tissue are separated by endothelial barriers. Beneath the endothelial barriers the tissues are connected via circulation containing secreted factors and cells (e.g., tumor/immune cells).

Abstract: Techniques to identify a mechanism of action of a compound using network dysregulation are disclosed herein. An example method can include selecting at least a first interaction involving at least a first gene, determining a first n-dimensional probability density of gene expression levels for the first gene and one or more genes in a control state, determining a second n-dimensional probability density of gene expression levels for the first gene and one or more genes following treatment using at least one compound, estimating changes between the first probability density and the second probability density, and determining whether the estimated changes are statistically significant.

Abstract: A method of treating a patient suffering from multiple myeloma, comprising determining a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; determining a classification of the subject as a responder or non-responder to a therapy by a compound represented by structural formula (1); and administering a therapeutically effective amount of the compound represented by structural formula (1) or a pharmaceutically acceptable salt thereof.

Abstract: The present disclosure provides, inter alia, scaffolds and compounds having the structure: Also provided are compositions containing a pharmaceutically acceptable carrier and one or more compounds according to the present disclosure. Further provided are methods for treating or ameliorating the effects of a cancer in a subject, methods for selectively killing a cancer cell, methods of modulating mTORC1/2 signaling activity in a cell, methods of modulating the activity of a Master Regulator for MycN in a subject having MycN-amplified neuroblastoma (MycNAMP NBL), methods of selectively treating or ameliorating effects of a cancer in a subject in need thereof, and platforms and methods for identifying a compound that induces degradation of a cancer-related protein. Also provided are kits comprising a compound or a pharmaceutical composition according to the present disclosure. Methods for treating cancers and methods for modulating MYC Master Regulators using other compounds are also provided.

Abstract: Techniques to identify a mechanism of action of a compound using network dysregulation are disclosed herein. An example method can include selecting at least a first interaction involving at least a first gene, determining a first n-dimensional probability density of gene expression levels for the first gene and one or more genes in a control state, determining a second n-dimensional probability density of gene expression levels for the first gene and one or more genes following treatment using at least one compound, estimating changes between the first probability density and the second probability density, and determining whether the estimated changes are statistically significant.

Abstract: Methods for determining regulon enrichment in gene expression signatures are disclosed herein. An example method can include obtaining a set of transcriptional targets of a regulon. The method can include obtaining a gene expression signature by comparing a gene expression profile of a test sample to gene expression profiles of a plurality of samples representing control phenotypes. The method can include calculating a regulon enrichment score for each regulon in the gene expression signature. The method can including determining whether a number of control samples in the control phenotypes is above a predetermined threshold to support evaluation of statistical significance using permutation analysis. The method can include, in response to determining that the number of control samples is above the predetermined threshold, calculating a significance value by comparing each regulon enrichment score to a null model.

Abstract: Techniques to profile a disease or a disorder (e.g., a tumor) based on a protein activity signature are disclosed herein. An example method can include measuring quantitatively protein activity of a plurality of master regulator proteins in a sample from a disease or disorder; and profiling the tumor from the quantitative protein activity of the master regulator proteins. Also disclosed are methods of identifying a compound or compounds that treats diseases or disorders (e.g., inhibit tumor cell growth).

Abstract: Methods for determining regulon enrichment in gene expression signatures are disclosed herein. An example method can include obtaining a set of transcriptional targets of a regulon. The method can include obtaining a gene expression signature by comparing a gene expression profile of a test sample to gene expression profiles of a plurality of samples representing control phenotypes. The method can include calculating a regulon enrichment score for each regulon in the gene expression signature. The method can including determining whether a number of control samples in the control phenotypes is above a predetermined threshold to support evaluation of statistical significance using permutation analysis. The method can include, in response to determining that the number of control samples is above the predetermined threshold, calculating a significance value by comparing each regulon enrichment score to a null model.

Abstract: Techniques to profile a disease or a disorder (e.g., a tumor) based on a protein activity signature are disclosed herein. An example method can include measuring quantitatively protein activity of a plurality of master regulator proteins in a sample from a disease or disorder; and profiling the tumor from the quantitative protein activity of the master regulator proteins. Also disclosed are methods of identifying a compound or compounds that treats diseases or disorders (e.g., inhibit tumor cell growth).

Abstract: Methods, pharmaceutical formulations and medicaments for treating prostate cancer or preventing the progression of a nonaggressive form of prostate cancer to an aggressive form, in a mammal, include a therapeutically effective amount of one or more active agents that reduce the expression or biological activity of both Forkhead box protein M1 (FOXM1) and Centromere protein F (CENPF) or biologically active fragments thereof or biologically active fragments thereof selected from the group consisting of an isolated shRNA, siRNA, antisense RNA, antisense DNA, Chimeric Antisense DNA/RNA, microRNA, and ribozymes that are sufficiently complementary to either a gene or an mRNA encoding either FOXM1 or CENPF proteins. A method is also presented for discovering synergistic master regulators of other phenotype transitions, wherein the master regulators are conserved among different species.

Abstract: Techniques to identify a mechanism of action of a compound using network dysregulation are disclosed herein. An example method can include selecting at least a first interaction involving at least a first gene, determining a first n-dimensional probability density of gene expression levels for the first gene and one or more genes in a control state, determining a second n-dimensional probability density of gene expression levels for the first gene and one or more genes following treatment using at least one compound, estimating changes between the first probability density and the second probability density, and determining whether the estimated changes are statistically significant.

Abstract: Methods for determining regulon enrichment in gene expression signatures are disclosed herein. An example method can include obtaining a set of transcriptional targets of a regulon. The method can include obtaining a gene expression signature by comparing a gene expression profile of a test sample to gene expression profiles of a plurality of samples representing control phenotypes. The method can include calculating a regulon enrichment score for each regulon in the gene expression signature. The method can including determining whether a number of control samples in the control phenotypes is above a predetermined threshold to support evaluation of statistical significance using permutation analysis. The method can include, in response to determining that the number of control samples is above the predetermined threshold, calculating a significance value by comparing each regulon enrichment score to a null model.

Abstract: Techniques to profile a disease or a disorder (e.g., a tumor) based on a protein activity signature are disclosed herein. An example method can include measuring quantitatively protein activity of a plurality of master regulator proteins in a sample from a disease or disorder; and profiling the tumor from the quantitative protein activity of the master regulator proteins. Also disclosed are methods of identifying a compound or compounds that treats diseases or disorders (e.g., inhibit tumor cell growth).

Abstract: Techniques for diagnosis of aggressive prostate cancer include determining a level of expression of each of the genes encoding (FOXM1) Forkhead box protein M1 and Centromere protein F (CENPF) in a test sample. If the level of expression of each of the FOXM1 and CENPF genes in the test sample is at least 35% higher than the corresponding level in a control sample, then it is determined that the subject has an aggressive form of prostate cancer or has a high risk of prostate cancer progressing to an aggressive form. Alternatively, if at least 50% of prostate cancer cells in the sample express both FOXM1 protein and CENPF protein at a composite score of at least 100 for each, then the above diagnosis is made. Composite score is calculated by multiplying a percent staining value by a staining intensity value.

Abstract: Methods, pharmaceutical formulations and medicaments for treating prostate cancer or preventing the progression of a nonaggressive form of prostate cancer to an aggressive form, in a mammal, include a therapeutically effective amount of one or more active agents that reduce the expression or biological activity of both Forkhead box protein M1 (FOXM1) and Centromere protein F (CENPF) or biologically active fragments thereof or biologically active fragments thereof selected from the group consisting of an isolated shRNA, siRNA, antisense RNA, antisense DNA, Chimeric Antisense DNA/RNA, microRNA, and ribozymes that are sufficiently complementary to either a gene or an mRNA encoding either FOXM1 or CENPF proteins. A method is also presented for discovering synergistic master regulators of other phenotype transitions, wherein the master regulators are conserved among different species.