Purpose:Small-cell neuroendocrine prostate cancer (SCNPC) exhibits an aggressive clinical course and incidence rates seem to be increasing following resistance to potent androgen receptor (AR) antagonists. Currently, treatment options are limited and few model systems are available to identify new approaches for treatment. We sought to evaluate commonalities between SCNPC and other aggressive neuroendocrine carcinomas to identify therapeutic targets. Experimental Design:We generated whole transcriptome...
Wed Apr 01, 2020 10:05
The present ReACT trial provides data from a small randomized controlled vaccination trial that in addition to other recent immunotherapy trials in glioblastoma allows sketching a rational, advanced trial design for the development of (immune) therapies in glioblastoma elaborating on but not restricting to biological monitoring and endpoints. See related article by Reardon et al., p. 1586
Wed Apr 01, 2020 10:05
Purpose:This study aims to provide comprehensive insights into longitudinal immune landscape in acute myeloid leukemia (AML) development and treatment, which may contribute to predict prognosis and guide clinical decisions. Experimental Design:Periphery blood samples from 79 patients with AML (at diagnosis or/and after chemotherapy or at relapse) and 24 healthy controls were prospectively collected. We performed phenotypic and functional analysis of various lymphocytes through multiparametric flow...
Wed Apr 01, 2020 10:05
KRAS G12C inhibitors have shown promise in KRAS G12C–mutant lung cancer but intrinsic and acquired resistance are common. Cotreatment with inhibitors of the protein phosphatase SHP2 can abrogate the adaptive response of cancer cells to KRAS inhibitors resulting in greater suppression of MAPK signaling and enhanced tumor growth inhibition. See related article by Ryan et al., p. 1633
Wed Apr 01, 2020 10:05
Purpose:Despite its enormous successes, the overall response rate of cancer immunotherapy remains suboptimal, especially in breast cancer. There is an increased interest in combining immune checkpoint inhibitor with targeted agents to enhance antitumor effect. Anti-angiogenic drugs have been shown to synergize with immune checkpoint blockades, but the optimal setting for combining these two modalities and the underlying mechanisms of synergistic responses are not fully understood. Experimental...
Wed Apr 01, 2020 10:05
The progression of multiple myeloma, a hematologic malignancy characterized by unregulated plasma cell growth, is associated with increasing innate and adaptive immune system dysfunction, notably in the T-cell repertoire. Although treatment advances in multiple myeloma have led to deeper and more durable clinical responses, the disease remains incurable for most patients. Therapeutic strategies aimed at overcoming the immunosuppressive tumor microenvironment and activating the host immune system...
Wed Apr 01, 2020 10:05
Wed Apr 01, 2020 10:05
Purpose:This two-part phase Ib trial determined the maximum tolerated dose (MTD) of the combination of trifluridine/tipiracil (FTD/TPI) and irinotecan in patients with advanced gastrointestinal tumors, and evaluated the safety, pharmacokinetics, and antitumor activity of the FTD/TPI, irinotecan, and bevacizumab triplet combination in previously treated metastatic colorectal cancer (mCRC). Patients and Methods:Dose escalation (3+3 design) in advanced gastrointestinal tumors was followed by expansion...
Wed Apr 01, 2020 10:05
Purpose:Emergence of mismatch repair (MMR) deficiency is a frequent mechanism of acquired resistance to the alkylating chemotherapeutic temozolomide (TMZ) in gliomas. Poly(ADP-ribose) polymerase inhibitors (PARPi) have been shown to potentiate TMZ cytotoxicity in several cancer types, including gliomas. We tested whether PARP inhibition could re-sensitize MSH6-null MMR-deficient gliomas to TMZ, and assessed the role of the base excision repair (BER) DNA damage repair pathway in PARPi-mediated effects....
Wed Apr 01, 2020 10:05
Purpose:To characterize the population pharmacokinetics of cyclophosphamide, active 4-hydroxy-cyclophosphamide (4OH-CTX), and inactive carboxyethylphosphoramide mustard (CEPM), and their associations with hematologic toxicities in infants and young children with brain tumors. To use this information to provide cyclophosphamide dosing recommendations in this population. Patients and Methods:Patients received four cycles of a 1-hour infusion of 1.5 g/m2 cyclophosphamide. Serial samples were collected...
Wed Apr 01, 2020 10:05
Purpose:Long noncoding RNAs (lncRNA) have been observed in various cancer types. Our bioinformatic analysis of existing databases demonstrated overexpression of lncRNA THAP9-AS1 in pancreatic ductal adenocarcinoma (PDAC). We aimed to investigate the roles and mechanisms of THAP9-AS1 in PDAC. Experimental Design:The overexpression of THAP9-AS1 in samples of patients with pancreatic cancer was characterized and was associated with clinical outcomes. The nonprotein coding property of the THAP9-AS1...
Wed Apr 01, 2020 10:05
Purpose:The STAKT study examined short-term exposure (4.5 days) to the oral selective pan-AKT inhibitor capivasertib (AZD5363) to determine if this drug can reach its therapeutic target in sufficient concentration to significantly modulate key biomarkers of the AKT pathway and tumor proliferation. Patients and Methods:STAKT was a two-stage, double-blind, randomized, placebo-controlled, "window-of-opportunity" study in patients with newly diagnosed ER+ invasive breast cancer. Stage 1 assessed capivasertib...
Wed Apr 01, 2020 10:05
Purpose:Rindopepimut is a vaccine targeting the tumor-specific EGF driver mutation, EGFRvIII. The ReACT study investigated whether the addition of rindopepimut to standard bevacizumab improved outcome for patients with relapsed, EGFRvIII-positive glioblastoma. Patients and Methods:In this double-blind, randomized, phase II study (NCT01498328) conducted at 26 hospitals in the United States, bevacizumab-naïve patients with recurrent EGFRvIII-positive glioblastoma were randomized to receive rindopepimut...
Wed Apr 01, 2020 10:05
Purpose:To evaluate the safety and feasibility of preoperative locoregional cytokine therapy (IRX-2 regimen) in early-stage breast cancer, and to evaluate for intratumoral and peripheral immunomodulatory activity. Patients and Methods:Sixteen patients with stage I–III early-stage breast cancer (any histology type) indicated for surgical lumpectomy or mastectomy were enrolled to receive preoperative locoregional immunotherapy with the IRX-2 cytokine biological (2 mL subcutaneous x 10 days to periareolar...
Wed Apr 01, 2020 10:05
Purpose:Patients with metastatic prostate cancer are increasingly presenting with treatment-resistant, androgen receptor–negative/low (AR–/Low) tumors, with or without neuroendocrine characteristics, in processes attributed to tumor cell plasticity. This plasticity has been modeled by Rb1/p53 knockdown/knockout and is accompanied by overexpression of the pluripotency factor, Sox2. Here, we explore the role of the developmental transcription factor Sox9 in the process of prostate cancer therapy response...
Wed Apr 01, 2020 10:05
Purpose:Immunogenicity derived from the murine scFv, a major molecular compomemt of chimeric antigen receptors (CARs), may limit the persistence of CAR T cells, resulting in tumor relapse of patients in complete remission (CR). In this study, we developed a humanized anti-CD19 scFv CAR-T (hCAR-T) to treat patients with relapsed/refractory acute lymphoblastic leukemia (r/r ALL). Patients and Methods:In this one-arm, open-labeled study, we infused the T cells modified with hCAR to patients with r/r...
Wed Apr 01, 2020 10:05
Purpose:PI3K signaling is a common feature of B-cell neoplasms, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL), and PI3K inhibitors have been introduced into the clinic. However, there remains a clear need to develop new strategies to target PI3K signaling. PI3K activity is countered by Src homology domain 2-containing inositol-5'-phosphatase 1 (SHIP1) and, here, we have characterized the activity of a novel SHIP1 activator, AQX-435, in preclinical models of...
Wed Apr 01, 2020 10:05
Purpose:To determine the efficacy of the therapeutic DNA vaccine GX-188E for inducing regression of cervical intraepithelial neoplasia (CIN) 3. Patients and Methods:We conducted a prospective, randomized, multicenter, open-label, phase II clinical trial of GX-188E in CIN3 patients positive for human papillomavirus (HPV) type 16/18. The primary endpoint was to determine the histopathologic regression to ≤CIN1 at visit seven (V7; 20 weeks after the first GX-188E injection), and an extension study...
Wed Apr 01, 2020 10:05
Purpose:Immune components of the tumor microenvironment (TME) have been associated with disease outcome. We prospectively evaluated the association of an immune-related gene signature (GS) with clinical outcome in melanoma and non–small cell lung cancer (NSCLC) tumor samples from two phase III studies. Experimental Design:The GS was prospectively validated using an adaptive signature design to optimize it for the sample type and technology used in phase III studies. One-third of the samples were...
Wed Apr 01, 2020 10:05
Purpose:TRK inhibitors achieve marked tumor-agnostic efficacy in TRK fusion–positive cancers and consequently are now an established standard of care. Little is known, however, about the demographics, outcomes, response to alternative standard therapies, or genomic characteristics of TRK fusion–positive cancers. Experimental Design:Utilizing a center-wide screening program involving more than 26,000 prospectively sequenced patients, genomic and clinical data from all cases with TRK fusions were...
Wed Apr 01, 2020 10:05
Purpose:Glioblastoma (GBM) is one of the most aggressive and lethal cancer types in humans. The standard treatment approach is surgery followed by chemoradiation. However, the molecular mechanisms of innate tumor radioresistance remain poorly understood. Experimental Design:We tested the expression of Smoothened (Smo) in primary and recurrent GBM tissues and cells. Then, we determined radiation effectiveness against primary and recurrent GBM cells. Lastly, the functional role of Smo in GBM radioresistance...
Wed Apr 01, 2020 10:05
Purpose:Although KRAS represents the most commonly mutated oncogene, it has long been considered an "undruggable" target. Novel covalent inhibitors selective for the KRASG12C mutation offer the unprecedented opportunity to target KRAS directly. However, prior efforts to target the RAS–MAPK pathway have been hampered by adaptive feedback, which drives pathway reactivation and resistance. Experimental Design:A panel of KRASG12C cell lines were treated with the KRASG12C inhibitors ARS-1620 and AMG...
Wed Apr 01, 2020 10:05
Purpose:Immune-checkpoint inhibitors have shown therapeutic efficacy in various malignant diseases. However, anti-programmed death (PD)-1 therapy has not shown clinical efficacy in multiple myeloma. Experimental Design:Bone marrow (BM) mononuclear cells were obtained from 77 newly diagnosed multiple myeloma patients. We examined the expression of immune-checkpoint receptors in BM CD8+ T cells and their functional restoration by ex vivo treatment with anti–PD-1 and TGFβ inhibitors. Results:We...
Wed Apr 01, 2020 10:05
Purpose:Tumor cells from patients with lung cancer are expelled from the primary tumor into the blood, but difficult to detect in the peripheral circulation. We studied the release of circulating tumor cells (CTCs) during surgery to test the hypothesis that CTC counts are influenced by hemodynamic changes (caused by surgical approach) and manipulation. Experimental Design:Patients undergoing video-assisted thoracic surgery (VATS) or open surgery for (suspected) primary lung cancer were included....
Wed Apr 01, 2020 10:05
Wed Apr 01, 2020 10:05
Antibody–peptide epitope conjugates (APEC) can reprogram surface antigenicity of tumor cells.
Wed Apr 01, 2020 10:05
A lentiviral-barcoding approach using mouse embryonic cells allows driver-mutation identification.
Wed Apr 01, 2020 10:05
RET alterations have been characterized as oncogenic drivers in multiple cancers. The clinical validation of highly selective RET inhibitors demonstrates the utility of specific targeting of aberrantly activated RET in patients with cancers such as medullary thyroid cancer or non–small cell lung cancer. The remarkable responses observed have opened the field of RET-targeted inhibitors. In this review, we seek to focus on the impact of therapeutic RET targeting in cancers. Significance:Successful...
Wed Apr 01, 2020 10:05
Group 2 innate lymphoid cells (ILC2) exerted antitumor effects in pancreatic adenocarcinomas.
Wed Apr 01, 2020 10:05
The Pan-Cancer Analysis of Whole Genomes project—the largest investigation of whole tumor genomes to date—has laid bare characteristic DNA aberrations responsible for cancer's development and helped unravel mutational processes that shape tumor evolution.
Wed Apr 01, 2020 10:05
Primary resistance to CD19-directed chimeric antigen receptor T-cell therapy (CART19) occurs in 10% to 20% of patients with acute lymphoblastic leukemia (ALL); however, the mechanisms of this resistance remain elusive. Using a genome-wide loss-of-function screen, we identified that impaired death receptor signaling in ALL led to rapidly progressive disease despite CART19 treatment. This was mediated by an inherent resistance to T-cell cytotoxicity that permitted antigen persistence and was subsequently...
Wed Apr 01, 2020 10:05
The recently approved federal budget for the current fiscal year includes a $297 million funding boost for the NCI, allowing it to fund more than 125 additional competing grants. Although the move reverses a decade of decreases in R01 paylines, competition for grants is expected to remain intense.
Wed Apr 01, 2020 10:05
The structure of CD20 with the antibody drug rituximab showed the binding mode and 2:2 stoichiometry.
Wed Apr 01, 2020 10:05
Angiosarcoma Project researchers have uncovered some details about the molecular underpinnings of angiosarcoma, pointing to potential therapeutic options. Their work also suggests that a research model based on direct patient participation can overcome common barriers to studying rare diseases.
Wed Apr 01, 2020 10:05
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