First-in-human phase 1 study of margetuximab (MGAH22), an Fc-modified chimeric monoclonal antibody, in patients with HER2-positive advanced solid tumors.

Background: Margetuximab is an anti-HER2 antibody that binds with elevated affinity to both the lower and higher affinity forms of CD16A, an Fc-receptor important for antibody dependent cell-mediated cytotoxicity (ADCC) against tumor cells. A Phase 1 study was initiated to evaluate the toxicity profile, maximum tolerated dose (MTD), pharmacokinetics, and antitumor activity of margetuximab in patients with HER2-overexpressing carcinomas.

Patients And Methods: Patients with HER2-positive breast or gastric cancer, or other carcinomas that overexpress HER2, for whom no standard therapy was available, were treated with margetuximab by intravenous infusion at doses of 0.

Circulating tumor cells: application as a biomarker for molecular characterization and predictor of survival in an all-comer solid tumor phase I clinical study.

Purpose: Clinical development of cancer drugs has a low success rate. Prognostic and predictive biomarkers using minimally invasive approaches hold promise for increasing the probability of success by enabling disease characterization, patient selection and early detection of drug treatment effect. Enumeration and molecular characterization of circulating tumor cells (CTC) may address some of these needs, and thus were evaluated for utility in a Phase I solid tumor clinical study.

Phase 1, open-label study of MEDI-547 in patients with relapsed or refractory solid tumors.

Background: Targeting the cell-surface receptor EphA2, which is highly expressed in some solid tumors, is a novel approach for cancer therapy. We aimed to evaluate the safety profile, maximum tolerated dose (MTD), pharmacokinetics, and antitumor activity of MEDI-547, an antibody drug conjugate composed of the cytotoxic drug auristatin (toxin) linked to a human anti-EphA2 monoclonal antibody (1C1), in patients with solid tumors relapsed/refractory to standard therapy.

Methods: In this phase 1, open-label study with planned dose-escalation and dose-expansion cohorts, patients received a 1-h intravenous infusion of MEDI-547 (0.

Phase I trial of anti-CD22 recombinant immunotoxin moxetumomab pasudotox (CAT-8015 or HA22) in patients with hairy cell leukemia.

Purpose: To conduct a phase I dose-escalation trial assessing safety and response of recombinant immunotoxin moxetumomab pasudotox (CAT-8015, HA22) in chemotherapy-resistant hairy cell leukemia (HCL).

Patients And Methods: Eligible patients had relapsed/refractory HCL after ≥ two prior therapies and required treatment because of abnormal blood counts. Patients received moxetumomab pasudotox 5 to 50 μg/kg every other day for three doses (QOD ×3), with up to 16 cycles repeating at ≥ 4-week intervals if patients did not experience disease progression or develop neutralizing antibodies.

CD22 as a target for cancer therapy.

Targeted therapies with monoclonal antibodies have been increasingly incorporated into the treatment for both lymphoid and myeloid hematological malignancies. Rituximab, the first approved monoclonal antibody for the treatment of cancer, has revolutionized our approach to the management of chronic lymphocytic leukemia and non-Hodgkin's lymphoma. However, there is still an unmet medical need for novel therapeutic approaches, especially for patients in the relapsed/refractory setting.

Thrombotic microangiopathy with targeted cancer agents.

Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are clinically similar disorders characterized by microvascular thrombosis, hemolysis, thrombocytopenia, and end-organ damage. Although they may present with overlapping symptoms, multiple etiologies have been proposed for these thrombotic microangiopathies (TMA). Chemotherapy-induced TMA, which has been described with the use of mitomycin, gemcitabine, and other drugs, has a poor prognosis.

Safety and immunologic response of a viral vaccine to prostate-specific antigen in combination with radiation therapy when metronomic-dose interleukin 2 is used as an adjuvant.

Purpose: We have previously reported on the safety and immunologic response of a poxvirus-based vaccine encoding prostate-specific antigen (PSA) used in combination with radiation therapy in patients with localized prostate cancer. We hypothesized that a "metronomic" dose of interleukin 2 (IL-2) as a biological adjuvant would cause less toxicity while maintaining immunologic response.

Experimental Design: Eighteen patients with localized prostate cancer were treated in a single-arm trial using previously established doses of vaccine and radiation therapy.

Ixabepilone in combination with capecitabine and as monotherapy for treatment of advanced breast cancer refractory to previous chemotherapies.

Purpose: To describe the considerations leading to marketing approval of ixabepilone in combination with capecitabine and as monotherapy for the treatment of advanced breast cancer that is refractory to other chemotherapies.

Experimental Design: Data from one randomized multicenter trial comparing combination therapy with ixabepilone and capecitabine to capecitabine alone were analyzed for support of the combination therapy indication. For monotherapy, a single-arm trial of ixabepilone was analyzed.

Transforming growth factor-beta receptor III downregulation in prostate cancer: is inhibin B a tumor suppressor in prostate?

The transforming growth factor-beta (TGF-beta) pathway plays dual roles in cancer, inhibiting epithelial cell growth under normal physiologic conditions, but promoting invasion and metastasis once growth inhibitory responses are lost. Two recent papers show that TGF-beta receptor III is the most common TGF-beta pathway component downregulated in prostate cancer. Here, we discuss the implications of these findings and what it may mean about the biology of this disease.

Transforming growth factor-beta1 effects on endothelial monolayer permeability involve focal adhesion kinase/Src.

Transforming growth factor (TGF)-beta1 activity has been shown to increase vascular endothelial barrier permeability, which is believed to precede several pathologic conditions, including pulmonary edema and vessel inflammation. In endothelial monolayers, TGF-beta1 increases permeability, and a number of studies have demonstrated the alteration of cell-cell contacts by TGF-beta1. We hypothesized that focal adhesion complexes also likely contribute to alterations in endothelial permeability.

SNIP1 is a candidate modifier of the transcriptional activity of c-Myc on E box-dependent target genes.

Using a yeast two-hybrid screen, we found that SNIP1 (Smad nuclear-interacting protein 1) associates with c-Myc, a key regulator of cell proliferation and transformation. We demonstrate that SNIP1 functions as an important regulator of c-Myc activity, binding the N terminus of c-Myc through its own C terminus, and that SNIP1 enhances the transcriptional activity of c-Myc both by stabilizing it against proteosomal degradation and by bridging the c-Myc/p300 complex. These effects of SNIP1 on c-Myc likely contribute to synergistic effects of SNIP1, c-Myc, and H-Ras in inducing formation of foci in an in vitro transformation assay and also in supporting anchorage-independent growth.

Mechanism of fibroblast growth factor-binding protein 1 repression by TGF-beta.

Transforming growth factor-beta (TGF-beta) is the prototypical member of a family of growth factors that play important roles in normal development and human diseases. We identified the gene for fibroblast growth factor-binding protein 1 (FGF-BP1) as being significantly repressed following TGF-beta treatment. FGF-BP1 is an extracellular matrix bound protein that enhances fibroblast growth factor (FGF) signaling.

RhoA modulates Smad signaling during transforming growth factor-beta-induced smooth muscle differentiation.

We recently reported that transforming growth factor (TGF)-beta induced the neural crest stem cell line Monc-1 to differentiate into a spindle-like contractile smooth muscle cell (SMC) phenotype and that Smad signaling played an important role in this phenomenon. In addition to Smad signaling, other pathways such as mitogen-activated protein kinase (MAPK), phosphoinositol-3 kinase, and RhoA have also been shown to mediate TGF-beta actions. The objectives of this study were to examine whether these signaling pathways contribute to TGF-beta-induced SMC development and to test whether Smad signaling cross-talks with other pathway(s) during SMC differentiation induced by TGF-beta.

Suv39h histone methyltransferases interact with Smads and cooperate in BMP-induced repression.

Smad proteins transduce signals from transforming growth factor-beta (TGF-beta) superfamily ligands to regulate the expression of target genes. In order to identify novel partners of Smad proteins in transcriptional regulation, we performed a two-hybrid screen using Smad5, a protein that is activated predominantly by bone morphogenetic protein (BMP) signaling. We identified an interaction between Smad5 and suppressor of variegation 3-9 homolog 2 (Suv39h2), a chromatin modifier enzyme.

Transforming growth factor-beta-induced differentiation of smooth muscle from a neural crest stem cell line.

During vascular development, nascent endothelial networks are invested with a layer of supporting cells called pericytes in capillaries or smooth muscle in larger vessels. The cellular lineage of smooth muscle precursors and factors responsible for regulating their differentiation remain uncertain. In vivo, cells derived from the multipotent neural crest can give rise to vascular smooth muscle in parts of the head and also the cardiac outflow tract.

Smad proteins regulate transcriptional induction of the SM22alpha gene by TGF-beta.

Smad proteins transduce signals from transforming growth factor-beta (TGF-beta) receptors and regulate transcription of target genes. TGF-beta is implicated in the regulation of the smooth muscle cell specific gene SM22alpha, but little is known about how Smads are involved in SM22alpha gene transcription. In this report, we demonstrate that TGF-beta activation of the SM22alpha promoter is Smad dependent in C3H10T1/2 cells, BALB 3T3 cells and neural crest Monc-1 cells.

A novel link between the proteasome pathway and the signal transduction pathway of the bone morphogenetic proteins (BMPs).

Background: The intracellular signaling events of the bone morphogenetic proteins (BMPs) involve the R-Smad family members Smad1, Smad5, Smad8 and the Co-Smad, Smad4. Smads are currently considered to be DNA-binding transcriptional modulators and shown to recruit the master transcriptional co-activator CBP/p300 for transcriptional activation. SNIP1 is a recently discovered novel repressor of CBP/p300.

Disruption of acvrl1 increases endothelial cell number in zebrafish cranial vessels.

The zebrafish mutant violet beauregarde (vbg) can be identified at two days post-fertilization by an abnormal circulation pattern in which most blood cells flow through a limited number of dilated cranial vessels and fail to perfuse the trunk and tail. This phenotype cannot be explained by caudal vessel abnormalities or by a defect in cranial vessel patterning, but instead stems from an increase in endothelial cell number in specific cranial vessels. We show that vbg encodes activin receptor-like kinase 1 (Acvrl1; also known as Alk1), a TGFbeta type I receptor that is expressed predominantly in the endothelium of the vessels that become dilated in vbg mutants.

Targeted mutagenesis of Smad1 reveals an essential role in chorioallantoic fusion.

The Smad family of intracellular signaling intermediates transduce signals downstream from the transforming growth factor beta (TGF-beta) family of receptor serine threonine kinases. The original member of this family, Smad1, has been shown to mediate signals from receptors for the bone morphogenetic proteins (BMPs), a large group of ligands in the TGF-beta superfamily that mediate important developmental events. We have targeted the Smad1 gene in mice and created mutants null at this locus.

Smad3/AP-1 interactions control transcriptional responses to TGF-beta in a promoter-specific manner.

Smad proteins transduce signals from TGF-beta receptors and regulate transcription of target genes either directly or in combination with other sequence-specific transcription factors. AP-1 sites and their cognate transcription factors also play important roles in the gene regulatory activities of TGF-beta. In this report, we have investigated the functional interactions of the Smad and AP-1 transcription factors.

Sorting nexin 6, a novel SNX, interacts with the transforming growth factor-beta family of receptor serine-threonine kinases.

Sorting nexins (SNX) comprise a family of proteins with homology to several yeast proteins, including Vps5p and Mvp1p, that are required for the sorting of proteins to the yeast vacuole. Human SNX1, -2, and -4 have been proposed to play a role in receptor trafficking and have been shown to bind to several receptor tyrosine kinases, including receptors for epidermal growth factor, platelet-derived growth factor, and insulin as well as the long form of the leptin receptor, a glycoprotein 130-associated receptor. We now describe a novel member of this family, SNX6, which interacts with members of the transforming growth factor-beta family of receptor serine-threonine kinases.

Transforming growth factor-beta receptor-associated protein 1 is a Smad4 chaperone.

Members of the transforming growth factor-beta (TGF-beta) superfamily signal through unique cell membrane receptor serine-threonine kinases to activate downstream targets. TRAP1 is a previously described 96-kDa cytoplasmic protein shown to bind to TGF-beta receptors and suggested to play a role in TGF-beta signaling. We now fully characterize the binding properties of TRAP1, and show that it associates strongly with inactive heteromeric TGF-beta and activin receptor complexes and is released upon activation of signaling.

A novel mitochondrial septin-like protein, ARTS, mediates apoptosis dependent on its P-loop motif.

Here we describe a protein product of the human septin H5/PNUTL2/CDCrel2b gene, which we call ARTS (for apoptosis-related protein in the TGF-beta signalling pathway). ARTS is expressed in many cells and acts to enhance cell death induced by TGF-beta or, to a lesser extent, by other apoptotic agents. Unlike related septin gene products, ARTS is localized to mitochondria and translocates to the nucleus when apoptosis occurs.