Neeta Somaiah

Universal Marker and Detection Tool for Human Sarcoma Circulating Tumor Cells

To date, no specific marker exists for the detection of circulating tumor cells (CTC) from different types of sarcomas, though tools are available for detection of CTCs in peripheral blood of patients with cancer for epithelial cancers. Here, we report cell-surface vimentin (CSV) as an exclusive marker on sarcoma CTC regardless of the tissue origin of the sarcoma as detected by a novel monoclonal antibody. Utilizing CSV as a probe, we isolated and enumerated sarcoma CTCs with high sensitivity and specificity from the blood of patients bearing different types of sarcoma, validating their phenotype by single cell genomic amplification, mutation detection, and FISH. Our results establish the first universal and specific CTC marker described for enumerating CTCs from different types of sarcoma, thereby providing a key prognosis tool to monitor cancer metastasis and relapse.

Molecularly Targeted Therapies in Non–Small-Cell Lung Cancer Annual Update 2014

There have been significant advances in the understanding of the biology and treatment of non-small-cell lung cancer (NSCLC) during the past few years. A number of molecularly targeted agents are in the clinic or in development for patients with advanced NSCLC. We are beginning to understand the mechanisms of acquired resistance after exposure to tyrosine kinase inhibitors in patients with oncogene addicted NSCLC. The advent of next-generation sequencing has enabled to study comprehensively genomic alterations in lung cancer. Finally, early results from immune checkpoint inhibitors are very encouraging. This review summarizes recent advances in the area of cancer genomics, targeted therapies, and immunotherapy.

Antiangiogenic agents in the management of non-small cell lung cancer: where do we stand now and where are we headed?

Several therapies targeting angiogenesis are currently in development for non-small cell lung cancer (NSCLC). This review discusses results of recent clinical trials evaluating chemotherapy plus antiangiogenic therapy for NSCLC. Bevacizumab, an anti-VEGF antibody, is currently approved for the treatment of advanced NSCLC in combination with carboplatin and paclitaxel. Completed phase III trials evaluating bevacizumab plus chemotherapy have shown prolonged progression-free survival; however, not all trials showed significant improvement in overall survival (OS). Phase III trials of the tyrosine kinase inhibitors (TKIs) vandetanib and sorafenib and the vascular disrupting agent ASA404 also failed to improve OS compared with chemotherapy alone. Clinical trials are ongoing involving several new antiangiogenic therapies, including ramucirumab, aflibercept, cediranib, BIBF 1120, sunitinib, pazopanib, brivanib, ABT-869, axitinib, ABT-751, and NPI-2358; several of these agents have shown promising phase I/II results. Results from recently completed and ongoing phase III trials will determine if these newer antiangiogenic agents will be incorporated into clinical practice.

Novel systemic therapies in advanced liposarcoma: A review of recent clinical trial results

Liposarcoma is one of the most common adult soft tissue sarcomas an consists of three histologic subtypes (well and dedifferentiated, myxoid/round cell, and pleomorphic). Surgery is the mainstay of treatment for localized disease; however for unresectable or metastatic disease, effective treatment options are currently limited. In the past decade, a better understanding of the distinct genetic and molecular aberrations for each of the three histologic subtypes has led to the development of several novel systemic therapies. Data from phase I and early phase II clinical trials have been reported. Despite challenges with conducting clinical trials in liposarcoma, preliminary results for several of these novel, biology-driven therapies are encouraging.

NY-ESO-1 (CTAG1B) expression in mesenchymal tumors

New York esophageal squamous cell carcinoma 1 (NY-ESO-1, CTAG1B) is a cancer-testis antigen and currently a focus of several targeted immunotherapeutic strategies. We performed a large-scale immunohistochemical expression study of NY-ESO-1 using tissue microarrays of mesenchymal tumors from three institutions in an international collaboration. A total of 1132 intermediate and malignant and 175 benign mesenchymal lesions were enrolled in this study. Immunohistochemical staining was performed on tissue microarrays using a monoclonal antibody for NY-ESO-1. Among mesenchymal tumors, myxoid liposarcomas showed the highest positivity for NY-ESO-1 (88%), followed by synovial sarcomas (49%), myxofibrosarcomas (35%), and conventional chondrosarcomas (28%). Positivity of NY-ESO-1 in the remaining mesenchymal tumors was consistently low, and no immunoreactivity was observed in benign mesenchymal lesions. On the basis of these findings, nearly 90% of myxoid liposarcomas, as well as a significant proportion of synovial sarcomas, myxofibrosarcomas, and conventional chondrosarcomas are good candidates for immunotherapy targeting NY-ESO-1.

Analysis of the Intratumoral Adaptive Immune Response in Well Differentiated and Dedifferentiated Retroperitoneal Liposarcoma

Treatment options are limited in well differentiated (WD) and dedifferentiated (DD) retroperitoneal liposarcoma. We sought to study the intratumoral adaptive immune response and explore the potential feasibility of immunotherapy in this disease. Tumor-infiltrating lymphocytes (TILs) were isolated from fresh surgical specimens and analyzed by flow cytometry for surface marker expression. Previously reported immune cell aggregates known as tertiary lymphoid structures (TLS) were further characterized by immunohistochemistry. In all fresh tumors, TILs were found. The majority of TILs were CD4 T cells; however cytotoxic CD8 T cells were also seen (average: 20% of CD3 T cells). Among CD8 T cells, 65% expressed the immune checkpoint molecule PD-1. Intratumoral TLS may be sites of antigen presentation as DC-LAMP positive, mature dendritic cells were found juxtaposed next to CD4 T cells. Clinicopathologic correlation, however, demonstrated that presence of TLS was associated with worse recurrence-free survival in WD disease and worse overall survival in DD disease. Our data suggest that an adaptive immune response is present in WD/DD retroperitoneal liposarcoma but may be hindered by TLS, among other possible microenvironmental factors; further investigation is needed. Immunotherapy, including immune checkpoint blockade, should be evaluated as a treatment option in this disease.

New drugs and combinations for the treatment of soft-tissue sarcoma: a review

Sarcomas are a heterogeneous group of solid tumors arising from either soft tissues or bone, accounting for approximately 1% of all cancers in adults. Management of these diseases has changed little over the past 10 years, with the exception of treatment of gastrointestinal stromal tumors. Reasons for this stagnation include multiple histologies commonly grouped together in clinical trials limiting the understanding of benefit of treatment and limited investigation of molecular targeted therapies. More recently, advances in molecular pathogenesis, the advent of novel and targeted therapeutics, and increasing collaborations between sarcoma investigators has helped move the field forward in the right direction. Here, we review the recent data on novel agents tested for the management of adult soft-tissue sarcomas, excluding gastrointestinal stromal tumors.

A tabulated summary of targeted and biologic therapies for non-small-cell lung cancer.

The current pace of development of targeted agents in lung cancer is unprecedented. This rapid pace of development is facilitated by the identification of novel targets, development of new ways of inhibiting older and more familiar targets and some very innovative therapeutic engineering that allows us to inhibit multiple targets simultaneously. In this tabulated summary of over 320 targeted therapies currently in practice and in clinical trials for patients with lung cancer are listed. Given that the information included is constantly changing, the readers are encouraged to ascertain the current status of the ongoing clinical trials by checking the clinicaltrials.gov website. To facilitate this, a hyperlink for each agent is inserted in the left hand column of this reference tool. Compounds in pre-clinical development that have not yet entered clinical trials are not listed. Target therapies that are in clinical development but not enrolling lung cancer patients are also not included. Save for these exceptions the list is intended to be comprehensive. In conclusion, there are a plethora of novel agents currently in development for lung cancer. The emergence of these agents offers hope to a group of patients for whom progress has been slow until now. However dramatic improvements in survival have already been made in specific subsets of patients and this pace of advancements is only expected to accelerate dramatically for the foreseeable future. Clinical Lung Cancer, Vol. 15, No. 1, 21-51 a 2014 Elsevier Inc. All rights reserved.

Targeted therapies for sarcomas: New roles for the pathologist

Sarcomas are a heterogeneous family of mesenchymal malignancies that employ an impressive variety of pathogenetic mechanisms. The traditional role of the pathologist in this field has been to ensure accurate diagnosis and histological grading to direct therapy. More recently, with the advent of targeted therapies directed at particular molecular alterations, the role of the pathologist has expanded and increased awareness of the genetic features of sarcomas is needed to deliver optimal multidisciplinary care. This review discusses these trends and briefly enumerates many of the molecular derangements and targeted agents currently used or under investigation in soft tissue sarcoma. A few sarcomas are highlighted in more detail to illustrate how pathologists can exert positive influence on patient care – not just through diagnosis and grading, but also with molecular characterizations. Featured sarcomas include alveolar soft part sarcoma, dermatofibrosarcoma protuberans, gastrointestinal stromal tumour, inflammatory myofibroblastic tumour and PEComas.

Phase I Trial of the Human Double Minute 2 Inhibitor MK-8242 in Patients With Advanced Solid Tumors.

Purpose To evaluate MK-8242 in patients with wild-type TP53 advanced solid tumors. Patients and Methods MK-8242 was administered orally twice a day on days 1 to 7 in 21-day cycles. The recommended phase II dose (RP2D) was determined on the basis of safety, tolerability, pharmacokinetics (PK), and by mRNA expression of the p53 target gene pleckstrin homology-like domain, family A, member 3 ( PHLDA3). Other objectives were to characterize the PK/pharmacodynamic (PD) relationship, correlate biomarkers with response, and assess tumor response. Results Forty-seven patients received MK-8242 across eight doses that ranged from 60 to 500 mg. Initially, six patients developed dose-limiting toxicities (DLTs): grade (G) 2 nausea at 120 mg; G3 fatigue at 250 mg; G2 nausea and G4 thrombocytopenia at 350 mg; and G3 vomiting and G3 diarrhea at 500 mg. DLT criteria were revised to permit management of GI toxicities. Dosing was resumed at 400 mg, and four additional DLTs were observed: G4 neutropenia and G4 thrombocytopenia at 400 mg and G4 thrombocytopenia (two patients) at 500 mg. Other drug-related G3 and G4 events included anemia, leukopenia, pancytopenia, nausea, hyperbilirubinemia, hypophosphatemia, and anorexia. On the basis of safety, tolerability, PK, and PD, the RP2D was established at 400 mg (15 evaluable patients experienced two DLTs). PK for 400 mg (day 7) showed Cmax 3.07 μM, Tmax 3.0 hours, t1/2 (half-life) 6.6 hours, CL/F (apparent clearance) 28.9 L/h, and Vd/F (apparent volume) 274 L. Blood PHLDA3 mRNA expression correlated with drug exposure ( R2 = 0.68; P < .001). In 41 patients with postbaseline scans, three patients with liposarcoma achieved a partial response (at 250, 400, and 500 mg), 31 showed stable disease, and eight had progressive disease. In total, 27 patients with liposarcoma had a median progression-free survival of 237 days. Conclusion At the RP2D of 400 mg twice a day, MK-8242 activated the p53 pathway with an acceptable safety and tolerability profile. The observed clinical activity (partial response and prolonged progression-free survival) provides an impetus for further study of HDM2 inhibitors in liposarcoma.