Cancer treatments have evolved from indiscriminate cytotoxic agents to selective genome- and immune-targeted drugs that have transformed outcomes for some malignancies. 1 Tumor complexity and heterogeneity suggest that the “precision medicine” paradigm of cancer therapy requires treatment to be personalized to the individual patient. 2 – 6 To date, precision oncology trials have been based upon molecular matching with predetermined monotherapies. 7 – 14 Several of these trials have been hindered by very low matching rates, often in the 5–10% range, 15 and low response rates. Low matching rates may be due to the use of limited gene panels, restrictive molecular matching algorithms, lack of drug availability or the deterioration and death of end-stage patients before therapy can be implemented. We hypothesized that personalized treatment with combination therapies would improve outcomes in patients with refractory malignancies. As a first test of this concept, we implemented a cross-institutional, prospective study (I-PREDICT, ) that used tumor DNA sequencing and timely recommendations for individualized treatment with combination therapies. We found that administration of customized multi-drug regimens was feasible, with 49% of consented patients receiving personalized treatment. Targeting of a larger fraction of identified molecular alterations, yielding a higher “matching score,” was correlated with significantly improved disease control rates, as well as longer progression-free and overall survival rates, as compared to when fewer somatic alterations were targeted. Our findings suggest that the current clinical trial paradigm for precision oncology, which pairs one driver mutation with one drug, may be optimized by treating molecularly complex and heterogeneous cancers with combinations of customized agents.

BackgroundTriple Negative subset of (TN) Breast Cancers (BC), a close associate of the basal-like subtype (with limited discordance) is an aggressive form of the disease which convey unpredictable, and poor prognosis due to limited treatment options and lack of proven effective targeted therapies.MethodsWe conducted an expression study of 240 formalin-fixed, paraffin-embedded (FFPE) primary biopsies from two cohorts, including 130 TN tumors, to identify molecular mechanisms of TN disease.ResultsThe annotation of differentially expressed genes in TN tumors contained an overrepresentation of canonical Wnt signaling components in our cohort and others. These observations were supported by upregulation of experimentally induced oncogenic Wnt/β-catenin genes in TN tumors, recapitulated using targets induced by Wnt3A. A functional blockade of Wnt/β-catenin pathway by either a pharmacological Wnt-antagonist, WntC59, sulidac sulfide, or β-catenin (functional read out of Wnt/β-catenin pathway) SiRNA mediated genetic manipulation demonstrated that a functional perturbation of the pathway is causal to the metastasis- associated phenotypes including fibronectin-directed migration, F-actin organization, and invasion in TNBC cells. A classifier, trained on microarray data from β-catenin transfected mammary cells, identified a disproportionate number of TNBC breast tumors as compared to other breast cancer subtypes in a meta-analysis of 11 studies and 1,878 breast cancer patients, including the two cohorts published here. Patients identified by the Wnt/β-catenin classifier had a greater risk of lung and brain, but not bone metastases.ConclusionThese data implicate transcriptional Wnt signaling as a hallmark of TNBC disease associated with specific metastatic pathways.

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These results suggest that laparoscopically assisted colon resection for malignant disease can be performed safely, with morbidity, mortality, and en bloc resections comparable with those of open laparotomy. Long-term (5-year) follow-up assessment shows similar outcomes in both groups of patients, demonstrating definite perioperative advantages with LA surgery and no perioperative or long-term disadvantages.

Carcinoma of unknown primary (CUP) is a rare and difficult-to-treat malignancy, the management of which might be improved by the identification of actionable driver mutations. We interrogated interrogated 54–70 genes in 442 patients with CUP using targeted clinical-grade, next-generation sequencing (NGS) of circulating tumor DNA (ctDNA). Overall, 80% of patients exhibited ctDNA alterations; 66%, ≥ 1 characterized alteration(s) excluding variants of unknown significance. TP53-associated genes were most commonly altered (37.8%) followed by genes involved in the MAPK pathway (31.2%), PI3K signaling (18.1%) and the cell cycle machinery (10.4%). Distinct genomic profiles were observed in 87.9% of CUP cases with 99.7% exhibiting potentially targetable alterations. An illustrative patient with dynamic changes in ctDNA content during therapy and a responder given a checkpoint inhibitor-based regimen because of a mismatch repair gene anomaly are presented. Our results demonstrate that ctDNA evaluation is feasible in CUP and that most patients harbor a unique somatic profile with pharmacologically actionable alterations, justifying the inclusion of non-invasive liquid biopsies in next-generation clinical trials.

Three GTPases, RAC, RHO, and Cdc42, play essential roles in coordinating many cellular functions during embryonic development, both in healthy cells and in disease conditions like cancers. We have presented patterns of distribution of the frequency of RAC1-alteration(s) in cancers as obtained from cBioPortal. With this background data, we have interrogated the various functions of RAC1 in tumors, including proliferation, metastasis-associated phenotypes, and drug-resistance with a special emphasis on solid tumors in adults. We have reviewed the activation and regulation of RAC1 functions on the basis of its sub-cellular localization in tumor cells. Our review focuses on the role of RAC1 in cancers and summarizes the regulatory mechanisms, inhibitory efficacy, and the anticancer potential of RAC1-PAK targeting agents.

Herein we report that, despite the similarity of Rac2 to Rac1 (92% amino acid identity), macrophages derived from Rac2؊/؊ mice, which continue to express Rac1, display a marked defect in ␣ v ␤ 3 /␣ v ␤ 5 and ␣ 4 ␤ 1 integrindirected migration measured on vitronectin and fibronectin fragments (FN-H296), respectively. In contrast, mouse embryo fibroblasts derived from the Rac2 knockout mice utilize Rac1 for migration via ␣ v ␤ 3 /␣ v ␤ 5 and ␣ 4 ␤ 1 . The genetic reconstitution of bone marrowderived macrophages (BMM) with Rac2 restores the integrin-dependent migration of Rac2-deficient macrophages on vitronectin (VN) and FN-H296. The levels of GTP-Rac2 generated upon specific integrin engagement in wild type macrophages parallels the phenotypic defect observed in Rac2-deficient macrophages; i.e. FN-H296,In a COS7 cell system, the expression of Syk kinase alone is sufficient to convert the ␣ 4 ␤ 1 migration response to Rac2 dependence. Therefore, we present the first evidence that the ␣ 4 ␤ 1 receptor in blood cells has evolved a Syk-Rac2 signaling axis to transmit signals required for integrin-directed migration suggesting that Syk kinase in part encodes myeloid Rac2 specificity in vivo.Cell migration is an essential process during development and wound healing. During cell migration coordination between membrane traffic, cell substrate adhesion, and actin polymerization and reorganization is required for protrusion of the leading edge. Actin cytoskeletal reorganization is regulated by Rho family GTPases and, with a contribution from the endocytic cycle, serves to extend the forward edge of mammalian cells (1, 2). The Rho family GTPases have been recognized as the regulators of signal transduction pathways that mediate distinct actin cytoskeleton changes required for cell migration (3, 4). The Rho family of small GTPases (including Rho, Rac, and Cdc42) comprises a complex group of at least 15 proteins critically involved as molecular switches in a large number of biochemical events in many cell types (5-7). Rac activation results from a combination of reduced association with GDP dissociation inhibitors and/or enhanced exchange of GDP to GTP promoted by guanine nucleotide exchange factors. Activated GTP-bound Rac proteins then transduce signals to downstream effector proteins. Finally, through association with GTPase-activating proteins, the GTP-bound small GTPase returns to an inactive GDP-bound form by hydrolysis of the bound GTP. Importantly, the events by which cell surface receptors orchestrate the activation of Rac are likely dependent upon the upstream activation of distinct protein-tyrosine kinases and the recruitment of specific adapter proteins to specific subcellular locals to transmit specific signals.One feature of the Rac proteins is their capacity to regulate the architecture of the actin cytoskeleton (3, 8 -11). Dynamic rearrangement of the actin cytoskeleton is key for morphological changes observed under conditions of adhesion to the extracellular matrix and for cell migration. The structure and ...

Oncoprotein CIP2A a Cancerous Inhibitor of PP2A forms an “oncogenic nexus” by virtue of its control on PP2A and MYC stabilization in cancer cells. The expression and prognostic function of CIP2A in different solid tumors including colorectal carcinoma, head & neck cancers, gastric cancers, lung carcinoma, cholangiocarcinoma, esophageal cancers, pancreatic carcinoma, brain cancers, breast carcinoma, bladder cancers, ovarian carcinoma, renal cell carcinomas, tongue cancers, cervical carcinoma, prostate cancers, and oral carcinoma as well as a number of hematological malignancies are just beginning to emerge. Herein, we reviewed the recent progress in our understanding of (1) how an “oncogenic nexus” of CIP2A participates in the tumorigenic transformation of cells and (2) how we can prospect/view the clinical relevance of CIP2A in the context of cancer therapy. The review will try to understand the role of CIP2A (a) as a biomarker in cancers and evaluate the prognostic value of CIP2A in different cancers (b) as a therapeutic target in cancers and (c) in drug response and developing chemo-resistance in cancers.