A bispecific antibody-drug conjugate targeting pCAD and CDH17 has antitumor activity and improved tumor-specificity.

P-cadherin (pCAD) and LI-cadherin (CDH17) are cell-surface proteins belonging to the cadherin superfamily that are both highly expressed in colorectal cancer. This co-expression profile presents a novel and attractive opportunity for a dual targeting approach using an antibody-drug conjugate (ADC). In this study, we used a unique avidity-driven screening approach to generate pCAD x CDH17 bispecific antibodies that selectively target cells expressing both antigens over cells expressing only pCAD or only CDH17.

SHP2 blockade enhances anti-tumor immunity via tumor cell intrinsic and extrinsic mechanisms.

SHP2 is a ubiquitous tyrosine phosphatase involved in regulating both tumor and immune cell signaling. In this study, we discovered a novel immune modulatory function of SHP2. Targeting this protein with allosteric SHP2 inhibitors promoted anti-tumor immunity, including enhancing T cell cytotoxic function and immune-mediated tumor regression.

A Proof of Concept for Biomarker-Guided Targeted Therapy against Ovarian Cancer Based on Patient-Derived Tumor Xenografts.

Advanced ovarian cancers are a leading cause of cancer-related death in women and are currently treated with surgery and chemotherapy. This standard of care is often temporarily successful but exhibits a high rate of relapse, after which, treatment options are few. Here we investigate whether biomarker-guided use of multiple targeted therapies, including small molecules and antibody-drug conjugates, is a viable alternative.

Tumor Intrinsic Efficacy by SHP2 and RTK Inhibitors in KRAS-Mutant Cancers.

, an oncogene mutated in nearly one third of human cancers, remains a pharmacologic challenge for direct inhibition except for recent advances in selective inhibitors targeting the G12C variant. Here, we report that selective inhibition of the protein tyrosine phosphatase, SHP2, can impair the proliferation of KRAS-mutant cancer cells and using cell line xenografts and primary human tumors. , sensitivity of KRAS-mutant cells toward the allosteric SHP2 inhibitor, SHP099, is not apparent when cells are grown on plastic in 2D monolayer, but is revealed when cells are grown as 3D multicellular spheroids.

SHP2 Inhibition Overcomes RTK-Mediated Pathway Reactivation in KRAS-Mutant Tumors Treated with MEK Inhibitors.

FGFR1 was recently shown to be activated as part of a compensatory response to prolonged treatment with the MEK inhibitor trametinib in several KRAS-mutant lung and pancreatic cancer cell lines. We hypothesize that other receptor tyrosine kinases (RTK) are also feedback-activated in this context. Herein, we profile a large panel of KRAS-mutant cancer cell lines for the contribution of RTKs to the feedback activation of phospho-MEK following MEK inhibition, using an SHP2 inhibitor (SHP099) that blocks RAS activation mediated by multiple RTKs.

A Maize Gene Regulatory Network for Phenolic Metabolism.

The translation of the genotype into phenotype, represented for example by the expression of genes encoding enzymes required for the biosynthesis of phytochemicals that are important for interaction of plants with the environment, is largely carried out by transcription factors (TFs) that recognize specific cis-regulatory elements in the genes that they control. TFs and their target genes are organized in gene regulatory networks (GRNs), and thus uncovering GRN architecture presents an important biological challenge necessary to explain gene regulation. Linking TFs to the genes they control, central to understanding GRNs, can be carried out using gene- or TF-centered approaches.

High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response.

Profiling candidate therapeutics with limited cancer models during preclinical development hinders predictions of clinical efficacy and identifying factors that underlie heterogeneous patient responses for patient-selection strategies. We established ∼1,000 patient-derived tumor xenograft models (PDXs) with a diverse set of driver mutations. With these PDXs, we performed in vivo compound screens using a 1 × 1 × 1 experimental design (PDX clinical trial or PCT) to assess the population responses to 62 treatments across six indications.

Non-specific symptomatogy presenting in a patient with Gaucher's disease creating a challenging diagnosis: a case report.

Gaucher's disease is the most common of the lysosomal storage diseases; however, with a current worldwide incidence of 1/75,000, it is still a rare occurrence. We present a case of Gaucher's disease type 1 in a Hispanic patient, the first incidence of this specific subtype of Gaucher's disease to be reported in Puerto Rico. Due to the patient's uncharacteristic presentation of negative initial bone marrow biopsy followed by the findings of Gaucher cells on splenic tissue examination, we investigate the specificity and sensitivity of various diagnostic methods to the disease as evidenced in the current literature.

Bilateral keratectasia after photorefractive keratectomy.

Purpose: To report the clinical features, management, and outcome of a patient who developed bilateral ectasia after photorefractive keratectomy (PRK).

Methods: Case report of a 35-year-old man who underwent bilateral PRK. Preoperative uncorrected visual acuity was 20/200 in the right eye and 20/100 in the left eye.

An imported case of Blastomyces dermatitidis infection in Mexico.

Blastomycosis is an acute or chronic primary infection of the respiratory system, endemic in North America (United States of America and Canada), Africa and Asia. We report a case in Mexico, in a three years old child who had been born in California and lived in Chicago, U.S.