GLP overexpression is associated with poor prognosis in Chronic Lymphocytic Leukemia and its inhibition induces leukemic cell death
Conclusion Taken together, these results indicate that GLP is associated with a worse prognosis in CLL, and that the inhibition of GLP/G9a influences CLL cell viability. Altogether, the present data demonstrate that these methyltransferases can be potential markers for disease progression, as well as a promising epigenetic target for CLL treatment and the prevention of disease evolution. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 12, 2018 Category: Drugs & Pharmacology Source Type: research

Phase I/II study of first-line combination therapy with sorafenib plus resminostat, an oral HDAC inhibitor, versus sorafenib monotherapy for advanced hepatocellular carcinoma in east Asian patients
SummaryPurpose: Resminostat is an oral inhibitor of class I, IIB, and IV histone deacetylases. This phase I/II study compared the safety and efficacy of resminostat plus sorafenib versus sorafenib monotherapy as first-line therapy for advanced hepatocellular carcinoma (HCC).Experimental design: In phase I, resminostat (400  mg or 600 mg/day on days 1 to 5 every 14 days) was administered with sorafenib (800 mg/day for 14 days) to determine the recommended dose for phase II. In phase II, patients were randomized (1:1) to sorafenib monotherapy or resminostat plus sorafenib. The primary endpoint was ti...
Source: Investigational New Drugs - September 10, 2018 Category: Drugs & Pharmacology Source Type: research

Identification of differentially expressed genes and signaling pathways using bioinformatics in interstitial lung disease due to tyrosine kinase inhibitors targeting the epidermal growth factor receptor
SummaryInterstitial lung disease (ILD) is a rare but lethal adverse effect of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) treatment. The specific mechanism of this disease is not fully understood. To systematically analyze genes associated with EGFR-TKI induced ILD, gene data of EGFR-TKI induced ILD were extracted initially using text mining, and then the intersection between genes from text mining and Gene Expression Omnibus (GEO) dataset was taken for further protein-protein interaction (PPI) analysis using String-bd database. Go ontology (GO) and pathway enrichment analysis was also conduct...
Source: Investigational New Drugs - September 10, 2018 Category: Drugs & Pharmacology Source Type: research

Novel N -1 substituted fluoroquinolones inhibit human topoisomerase I activity and exhibit anti-proliferative activity
SummaryFluoroquinolone-class agents selectively target the bacterial type IIA topoisomerases DNA gyrase and topoisomerase IV, with a few exceptions that target eukaryotic type IIA topoisomerases. Fluoroquinolones bind and stabilize type IIA topoisomerase-DNA covalent complexes that contain a double-strand break. This unique mode of action is referred to as ‘topoisomerase poisoning’. We discovered that two novel fluoroquinolones having aryl functionality at theN-1 position, UITT-3-217 (217) and UITT-3-227 (227), could inhibit the catalytic activity of human topoisomerase II without stabilizing topoisomerase-DNA ...
Source: Investigational New Drugs - September 10, 2018 Category: Drugs & Pharmacology Source Type: research

CDKI-73: an orally bioavailable and highly efficacious CDK9 inhibitor against acute myeloid leukemia
SummaryAcute myeloid leukemia (AML) is the most common form of acute leukemia with dismal long-term prognosis with age. The most aggressive subtype of AML is MLL-AML that is characterized by translocations of the mixed-lineage leukemia gene (MLL) and resistance to conventional chemotherapy. Cyclin dependent kinase 9 (CDK9) plays a crucial role in theMLL-driven oncogenic transcription, and hence, inhibiting activity of CDK9 has been proposed as a promising strategy for treatment of AML. We investigated the therapeutic potential of CDKI-73, one of the most potent CDK9 inhibitors, against a panel of AML cell lines and samples...
Source: Investigational New Drugs - September 8, 2018 Category: Drugs & Pharmacology Source Type: research

Ketoconazole plus Lenalidomide in patients with Castration-Resistant Prostate Cancer (CRPC): results of an open-label phase II study
Conclusion The combination of ketoconazole and lenalidomide was well tolerated but did not meet the primary endpoint of response, despite durable responses were observed in a selected group of patients. Although ketoconazole has now been replaced with more active novel agents, the combination of novel CYP-17 inhibitors with agents capable of modulating the immune system warrants further prospective investigation. NCT00460031. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 6, 2018 Category: Drugs & Pharmacology Source Type: research

Phase I study combining the aurora kinase a inhibitor alisertib with mFOLFOX in gastrointestinal cancer
SummaryOverexpression and cellular mis-localization  of aurora kinase A (AURKA) in gastrointestinal cancers results in chromosomal instability, activation of multiple oncogenic pathways, and inhibition of pro-apoptotic signaling. Inhibition of AURKA causes mitotic delays, severe chromosome congression, and activation of p53/p73 leading to cell death . Our preclinical data showed cooperative activity with the AURKA inhibitor alisertib and platinum agents in cell lines and xenografts, and suggested an optimal treatment window. Therefore, this study was designed to determine the maximum-tolerated dose (MTD) of alisertib ...
Source: Investigational New Drugs - September 6, 2018 Category: Drugs & Pharmacology Source Type: research

A phase I study of the farnesyltransferase inhibitor Tipifarnib in combination with the epidermal growth factor tyrosine kinase inhibitor Erlotinib in patients with advanced solid tumors
Conclusion The combination of tipifarnib and erlotinib was well tolerated. Erlotinib 150  mg once daily for 28 days combined with tipifarnib 300 mg twice daily for 21 days was identified as the recommended phase 2 dose. Tipifarnib is currently being evaluated inHRAS mutant tumors, providing a potential opportunity to further test this combination. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 31, 2018 Category: Drugs & Pharmacology Source Type: research

Preclinical assessment of histone deacetylase inhibitor quisinostat as a therapeutic agent against esophageal squamous cell carcinoma
SummaryEsophageal squamous cell carcinoma (ESCC) is one of the most serious life-threatening malignancies. Although chemotherapeutic targets and agents for ESCC have made much progress recently, the efficacy is still unsatisfactory. Therefore, there is still an unmet medical need for patients with ESCC. Here, we report the expression status of HDAC1 in human ESCC and matched paracancerous tissues, and the results indicated that HDAC1 was generally upregulated in ESCC specimens. Furthermore, we comprehensively assessed the anti-ESCC activity of a highly active HDAC1 inhibitor quisinostat. Quisinostat could effectively suppr...
Source: Investigational New Drugs - August 31, 2018 Category: Drugs & Pharmacology Source Type: research

Hexane partition from Annona crassiflora Mart. promotes cytotoxity and apoptosis on human cervical cancer cell lines
In this study the antineoplastic effect of crude extract and derived partitions fromA. crassiflora Mart in cervical cancer cell lines was evaluated. The crude extract significantly alters cell viability of cervical cancer cell lines as well as proliferation and migration, and induces cell death in SiHa cells. Yet, the combination of the crude extract with cisplatin leads to antagonistic effect. Importantly, the hexane partition derived from the crude extract presented cytotoxic effect bothin vitro andin vivo, and initiates cell responses, such as DNA damage (H2AX activity), apoptosis via intrinsic pathway (cleavage of casp...
Source: Investigational New Drugs - August 29, 2018 Category: Drugs & Pharmacology Source Type: research

Long-term adverse event: inflammatory orbitopathy induced by pembrolizumab in a patient with metastatic melanoma
SummaryThe recent advent of immune checkpoint inhibitors (ICI), including anti-programmed cell death 1 protein (anti-PD-1) agents has revolutionized the therapeutic approach of metastatic malignancies. Yet, ICI can disrupt immune tolerance resulting in enhanced immune activation in normal tissues with significant toxicity. A dysregulated activation of T-cells directed to normal tissues stands as the main mechanism of immune-related adverse events (irAE). To date, only two cases of immune-related inflammatory orbitopathy related to anti-PD-1 agents have been reported. This rare immune adverse event usually occurred early af...
Source: Investigational New Drugs - August 25, 2018 Category: Drugs & Pharmacology Source Type: research

A phase 1 trial of SGN-CD70A in patients with CD70-positive diffuse large B cell lymphoma and mantle cell lymphoma
Conclusions While modest single-agent activity was observed in heavily pretreated NHL patients, the applicability of SGN-CD70A is limited by the frequency and severity of thrombocytopenia, despite the long-term response with limited drug exposure. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 22, 2018 Category: Drugs & Pharmacology Source Type: research

Phase I study of S-1 plus paclitaxel combination therapy as a first-line treatment in elderly patients with advanced non-small cell lung cancer
In conclusion, the RD of both S-1 and paclitaxel was 80  mg/m2 in the combination therapy for chemotherapy-na ïve patients with advanced NSCLC. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 18, 2018 Category: Drugs & Pharmacology Source Type: research

A phase Ib study of BGJ398, a pan-FGFR kinase inhibitor in combination with imatinib in patients with advanced gastrointestinal stromal tumor
Conclusions Toxicity was encountered with the combination therapy of BGJ398 and imatinib. Due to withdrawal of sponsor support the study closed before the RP2D or dosing schedule of the combination therapy was identified. In heavily pre-treated patients, stable disease ≥ 32 weeks was observed in 3 of 12 evaluable patients. Trial Registration:NCT02257541. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 13, 2018 Category: Drugs & Pharmacology Source Type: research

The Monocarboxylate transporter inhibitor Quercetin induces intracellular acidification in a mouse model of Glioblastoma Multiforme: in-vivo detection using magnetic resonance imaging
SummaryThe response of tumor intracellular pH to a pharmacological challenge could help identify aggressive cancer. Chemical exchange saturation transfer (CEST) is an MRI contrast mechanism that is dependent on intracellular pH (pHi). pHi is important in the maintenance of normal cell function and is normally maintained within a narrow range by the activity of transporters located at the plasma membrane. In cancer, changes in pHi have been correlated with both cell proliferation and cell death. Quercetin is a bioflavonoid and monocarboxylate transporter (MCT) inhibitor. Since MCTs plays a significant role in maintaining pH...
Source: Investigational New Drugs - August 13, 2018 Category: Drugs & Pharmacology Source Type: research

Current status of androgen receptor-splice variant 7 inhibitor niclosamide in castrate-resistant prostate-cancer
SummaryCastrate-Resistant Prostate-Cancer (CRPC) is one of the most common malignancies occurring in men. Unfortunately, even if several recently approved agents clinically improved the outcome of CRPC patients, none of these is curative especially for a splice version of the Androgen Receptor (AR) AR-V7, which is a variant of the receptor constitutively activated and does not require the presence of androgens for the activation AR down-stream pathways. Since high AR-V7 expression is one of the most common features of CRPC, targeting this receptor variant is considered as one of the most promising strategies for treating t...
Source: Investigational New Drugs - August 7, 2018 Category: Drugs & Pharmacology Source Type: research

Phase II randomized, double-blind, placebo-controlled study of tivantinib in men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC)
Conclusions Tivantinib has mild toxicity and improved PFS in men with asymptomatic or minimally symptomatic mCRPC. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 7, 2018 Category: Drugs & Pharmacology Source Type: research

Global trends in the distribution of cancer types among patients in oncology phase I trials, 1991 –2015
Conclusions The distribution of cancer types among patients in phase I trials has changed. The comprehensive review of the distribution of solid tumor types could contribute to flexible trial designs and optimal patient recruitment. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 7, 2018 Category: Drugs & Pharmacology Source Type: research

Emerging roles of non-coding RNAs in the pathogenesis, diagnosis and prognosis of osteosarcoma
SummaryNon-coding RNAs (ncRNAs) have been found to play essential roles in various physiological and pathological processes. The involvement of ncRNAs in the development of osteosarcoma (OS) has been explored in recent years. In this review, we summarize the functions and mechanisms of microRNA, lncRNA and circRNA in the initiation and progression of OS. We specifically focused on their potential application in the diagnosis, prognosis and therapy of OS. This summary of current knowledge on the involvement of ncRNAs in OS will not only aid comprehension of the complex processes of OS initiation and progression but also con...
Source: Investigational New Drugs - August 6, 2018 Category: Drugs & Pharmacology Source Type: research

Characterization and phase I study of CLR457, an orally bioavailable pan-class I PI3-kinase inhibitor
Conclusion CLR457 clinical development was terminated due to poor tolerability and limited antitumor activity. These results emphasize the difficulty of achieving a wide therapeutic index when targeting all class I PI3K-isoforms. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 3, 2018 Category: Drugs & Pharmacology Source Type: research

Development of apratoxin S10 (Apra S10) as an anti-pancreatic cancer agent and its preliminary evaluation in an orthotopic patient-derived xenograft (PDX) model
SummaryDespite the significant progress in the field of cancer therapeutics, the incidence of pancreatic cancer (PC) has continuously increased. One possible mechanism for this increasing burden is impaired drug delivery and drug resistance resulting from a unique tumor microenvironment and genetic mutations. Apratoxins are potent anticancer agents and cotranslational translocation inhibitors with potential therapeutic applications to treat cancers with active secretory pathways. Here, we developed apratoxin S10 (Apra S10) as an anti-pancreatic cancer agent which potently inhibited the growth of both established and patien...
Source: Investigational New Drugs - August 3, 2018 Category: Drugs & Pharmacology Source Type: research

A natural compound derivative P-13 inhibits STAT3 signaling by covalently inhibiting Janus kinase 2
SummaryWe investigated the function and molecular mechanisms of 2-desoxy-4 β-propylcarbamate-pulchellin (P-13), a sesquiterpene lactone derivative of 2-desoxy-4-epi-pulchellin from the traditional Chinese medicinal herb Carpesium abrotanoides L, in regulating STAT3 signaling and cancer cell growth. We found that P-13 inhibited the IL-6-induced, as well as the constitutive , STAT3 activation in a dose and time-dependent manner. In vitro kinase activity analyses demonstrated that P-13 directly inhibited JAK2 kinase activity. The inhibitory effects of P-13 on JAK2/STAT3 signaling could be blocked by reducing agents dithi...
Source: Investigational New Drugs - August 3, 2018 Category: Drugs & Pharmacology Source Type: research

Sarcoid-like reaction mimicking disease progression in an ALK-positive lung cancer patient receiving lorlatinib
SummaryThe administration of target inhibitors is paramount to grant the longest survival in patients with ALK-positive non-small cell lung cancer (NSCLC). The eventual resistance to tyrosine kinase inhibitors (TKI) is monitored clinically and radiologically for prompt molecule shift to further generation TKI, if available. However, the early radiological detection of progression pattern (e.g. nodule onset) should be regarded with caution because overlaps exist with non-tumor cell proliferation and/or accumulation. Here we report the case of a stage IVALK-rearranged NSCLC patient exposed to serial crizotinib, brigatinib, c...
Source: Investigational New Drugs - August 1, 2018 Category: Drugs & Pharmacology Source Type: research

MET-targeting antibody (emibetuzumab) and kinase inhibitor (merestinib) as single agent or in combination in a cancer model bearing MET exon 14 skipping
Conclusions Data in this study support a clinical evaluation of merestinib in patients with MET exon 14 skipping (NCT02920996). As a type II MET kinase inhibitor, merestinib may provide a therapeutic option to treatment na ïve patients or to patients who progress on type I MET inhibitor treatment. Data also support clinical evaluation of the sequential combination of merestinib with emibetuzumab when patients progress on single agent merestinib. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 24, 2018 Category: Drugs & Pharmacology Source Type: research

Absorption, metabolism, and excretion of the antiemetic rolapitant, a selective neurokinin-1 receptor antagonist, in healthy male subjects
SummaryRolapitant is a neurokinin-1 receptor antagonist that is approved in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting (CINV) associated with initial and repeat courses of emetogenic cancer chemotherapy, including but not limited to highly emetogenic chemotherapy. Here, we assessed the absorption, metabolism, and excretion of14C-labeled rolapitant in healthy male subjects. Rolapitant was administered as a single 180-mg oral dose containing approximately 100  μCi of total radioactivity, with plasma, urine, and fecal samples collected at defined intervals afte...
Source: Investigational New Drugs - July 21, 2018 Category: Drugs & Pharmacology Source Type: research

Chemosensitivity of various peritoneal cancer cell lines to HIPEC and PIPAC: comparison of an experimental duplex drug to standard drug regimens in vitro
SummaryWe performed an in-vitro study testing the chemosensitivity of peritoneal cancer cell lines (SW620, HCT116, MKN45, 23,132/87, OAW42) to various cytostatic drug regimens. A duplex drug, characterized by reversible linking of the antimetabolites 2 ′-deoxy-5-fluorouridine (5-FdU) and 3’-C-ethynylcytidine (ECyd), was compared to oxaliplatin or to cisplatin plus doxorubicin. The experiments were designed to reflect the conditions of intraperitoneal chemotherapy. CASY® (Cell Analysis System) technology was used to compare the impact of incub ation temperature/duration and drug concentration on the viabilit...
Source: Investigational New Drugs - July 18, 2018 Category: Drugs & Pharmacology Source Type: research

Hand-foot-skin reaction of grade  ≥ 2 within sixty days as the optimal clinical marker best help predict survival in sorafenib therapy for HCC
SummaryBackground& Aims Sorafenib-related adverse events have been reported as clinical surrogates for treatment response in hepatocellular carcinoma (HCC); however, no consensus has been reached regarding the definition of responders. We evaluated the predictive abilities of different definitions for sorafenib response based on treatment-emergent adverse events, aiming to identify the most discriminatory one as a clinical marker.Methods From January 2010 to December 2014, 435 consecutive HCC patients treated with sorafenib were enrolled. Considering the type, severity and timing of adverse events, twelve different cat...
Source: Investigational New Drugs - July 18, 2018 Category: Drugs & Pharmacology Source Type: research

Design, synthesis and antiproliferative evaluation of novel sulfanilamide-1,2,3-triazole derivatives as tubulin polymerization inhibitors
SummaryMicrotubule as an important target in the cancer therapy was used to design novel tubulin polymerization inhibitors. Sulfanilamide-1,2,3-triazole hybrids were designed by a molecular hybridization strategy and their antiproliferative activity against three selected cancer cell lines (BGC-823, MGC-803 and SGC-7901) were evaluated. All sulfanilamide-1,2,3-triazole hybrids displayed potent inhibitory activity against all cell lines. In particular, compound10b showed the most excellent inhibitory effect against MGC-803 cells, with an IC50 value of 0.4 μM. Cellular mechanism studies elucidated that10b induced apoptosi...
Source: Investigational New Drugs - July 18, 2018 Category: Drugs & Pharmacology Source Type: research

Phase Ib trial combining capecitabine, erlotinib and bevacizumab in pancreatic adenocarcinoma - REBECA trial
Conclusions The study met the primary objective. RP2D was capecitabine 800  mg/m2 bid continuously, erlotinib 150  mg daily, and bevacizumab 10 mg/kg q 2 weeks. The regimen could be applied safely, but demonstrated limited efficacy. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 12, 2018 Category: Drugs & Pharmacology Source Type: research

The marine natural product Scalarin inhibits the receptor for advanced glycation end products (RAGE) and autophagy in the PANC-1 and MIA PaCa-2 pancreatic cancer cell lines
SummaryPancreatic cancer, the fourth leading cause of cancer death in the United States, has a negative prognosis because metastasis occurs before symptoms manifest. Although combination therapies are showing improvements in treatment, the survival rate for pancreatic cancer five years post diagnosis is only 8%, stressing the need for new treatments. The receptor for advanced glycation end products (RAGE) has recently emerged as a chemotherapeutic target in KRAS driven pancreatic cancers both for treatment and in chemoprevention. RAGE appears to be an important regulator of inflammatory, stress and survival pathways that l...
Source: Investigational New Drugs - July 12, 2018 Category: Drugs & Pharmacology Source Type: research

Phase I study of resminostat, an HDAC inhibitor, combined with S-1 in patients with pre-treated biliary tract or pancreatic cancer
In conclusion, regimen 3 was well tolerated by patients with pre-treated biliary tract or pancreatic cancer. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 11, 2018 Category: Drugs & Pharmacology Source Type: research

A phase 1b study of transforming growth factor-beta receptor I inhibitor galunisertib in combination with sorafenib in Japanese patients with unresectable hepatocellular carcinoma
Conclusions These data are consistent with the known safety profile for galunisertib and sorafenib and confirm tolerability of the recommended dose of galunisertib (150  mg twice daily for 14 days) in combination with sorafenib in Japanese patients with unresectable hepatocellular carcinoma. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 11, 2018 Category: Drugs & Pharmacology Source Type: research

A phase 1, first-in-human study of AMG 900, an orally administered pan-Aurora kinase inhibitor, in adult patients with advanced solid tumors
Conclusions AMG 900 40  mg/day with G-CSF had manageable toxicity and demonstrated single-agent activity in patients with heavily pretreated, chemotherapy-resistant ovarian cancer. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 7, 2018 Category: Drugs & Pharmacology Source Type: research

Leptomeningeal recurrence after long-term alectinib therapy for non-small cell lung cancer harboring an EML4-ALK fusion protein
SummaryThe recent approval of anaplastic lymphoma kinase (ALK) inhibitors for the treatment ofALK-rearranged non-small cell lung cancer (NSCLC) has dramatically transformed cancer therapy. However, leptomeningeal metastases (LM) are frequent and often devastating complications ofALK-rearranged NSCLC, and treatment against LM remains challenging. Herein we report a case of a 19-year-old male diagnosed withALK-rearranged NSCLC with LM. He experienced heavy treatment before introduction of alectinib therapy, which continued for approximately 5.5  years with marked efficacy. However, he experienced recurrence of a bulbar ...
Source: Investigational New Drugs - July 3, 2018 Category: Drugs & Pharmacology Source Type: research

Oral Metronomic Vinorelbine (OMV) in elderly or pretreated patients with advanced non small cell lung cancer: outcome and pharmacokinetics in the real world
Conclusions OMV produced non-negligible survival in patients and also showed stable long-term blood concentrations. The schedule of 20 –30 mg every other day without interruption gave good tolerability and clinical benefit. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 28, 2018 Category: Drugs & Pharmacology Source Type: research

Cabozantinib-induced serum creatine kinase elevation and musculoskeletal complaints
SummaryCabozantinib is a multikinase inhibitor approved for the treatment of metastatic medullary thyroid cancer and advanced renal cell carcinoma (RCC) in patients who have received prior anti-angiogenic therapy. While associations between serum creatine kinase (CK) elevations and other tyrosine kinase inhibitors used for the treatment of solid malignancies have been previously reported, we report a case of cabozantinib-associated CK elevation that was associated with musculoskeletal complaints by an RCC patient. Nine days following initiation of cabozantinib, the patient reported muscle cramps and serum CK had increased ...
Source: Investigational New Drugs - June 28, 2018 Category: Drugs & Pharmacology Source Type: research

Inhibition of SHP2 by new compounds induces differential effects on RAS/RAF/ERK and PI3K/AKT pathways in different cancer cell types
SummaryKinases and phosphatases are important players in growth signaling and are involved in cancer development. For development of targeted cancer therapy, attention is given to kinases rather than phosphatases inhibitors. Src homology region 2 domain-containing protein tyrosine phosphatase2 (SHP2) is overexpressed in different types of cancers. We investigated the SHP2-inhibitory effects of two new 5-aminosalicylate –4-thiazolinones in human cervical (HeLa) and breast (MCF-7& MDA-MB-231) cancer cells.In-silico molecular docking showed preferential affinity of the two compounds towards the catalytic over the al...
Source: Investigational New Drugs - June 27, 2018 Category: Drugs & Pharmacology Source Type: research

Proliferative CD8(+) PD-1(+) T-cell infiltration in a pembrolizumab-induced cutaneous adverse reaction
SummaryPembrolizumab, a humanized monoclonal immunoglobulin (Ig) G4 antibody that is directed against the human cell surface receptor PD-1, is a PD-1 pathway inhibitor that has been approved to treat various malignant diseases, including advanced non-small cell lung cancer (NSCLC). PD-1 is the major inhibitory receptor regulating T-cell exhaustion, and T-cells with high PD-1 expression lose their ability to eliminate cancer. PD-1 pathway blockade by pembrolizumab reinvigorates exhausted T-cells and restores their antitumor immune responses. However, reinvigorated T-cells also evoke immune-related adverse effects (irAEs), w...
Source: Investigational New Drugs - June 26, 2018 Category: Drugs & Pharmacology Source Type: research

Alteration of benzo(a)pyrene biotransformation by resveratrol in Apc Min/+ mouse model of colon carcinogenesis
In this study we investigated to ascertain whether the preventive effects of RVT on BaP-induced colon carcinogenesis is a result of altered BaP biotransformation by RVT. For the first group of mice, 100  μg BaP/kg bw was administered in peanut oil via oral gavage over a 60 day period. For the second group, 45 μg RVT/kg bw was co-administered with BaP. For the third group, RVT was administered for 1 week prior to BaP exposure. Blood, colon and liver were collected from control and BaP/RVT-trea ted mice at 60 days post-BaP& RVT exposure. We have assayed activities and expression (protein&am...
Source: Investigational New Drugs - June 22, 2018 Category: Drugs & Pharmacology Source Type: research

Euphol, a tetracyclic triterpene, from Euphorbia tirucalli induces autophagy and sensitizes temozolomide cytotoxicity on glioblastoma cells
In conclusion, euphol exerted in vitro and i n vivo cytotoxicity against glioma cells, through several cancer pathways, including the activation of autophagy-associated cell death. These findings provide experimental support for further development of euphol as a novel therapeutic agent for GBM, either alone or in combination chemotherapy. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 22, 2018 Category: Drugs & Pharmacology Source Type: research

Dual targeting of bromodomain-containing 4 by AZD5153 and BCL2 by AZD4320 against B-cell lymphomas concomitantly overexpressing c-MYC and BCL2
This study examined triple targeting of c-MYC, BCL2 and the B-cell receptor (BCR) signaling pathway for DHL and DEL. We first used AZD5153, a novel bivalent inhibitor for bromodomain-containing 4 (BRD4), in DHL- and DEL-derived cell lines, because BRD4 regulates disease type-oriented key molecules for oncogenesis. AZD5153 was more effective than conventional monovalent BRD4 inhibitors, JQ1 and I-BET151, in inhibiting cell proliferation of a DHL-derived cell line and two DEL-derived cell lines, with at least 10-fold lower half growth inhibitory concentrations. AZD5153 caused G1/S cell cycle blockade, while the apoptosis-ind...
Source: Investigational New Drugs - June 21, 2018 Category: Drugs & Pharmacology Source Type: research

Methionine gamma lyase from Clostridium sporogenes increases the anticancer effect of doxorubicin in A549 cells and human cancer xenografts
SummaryThe anti-cancer efficacy of methionine γ-lyase (MGL) fromClostridium sporogenes (C. sporogenes) is described. MGL was active against cancer models in vitro and in vivo. The calculated EC50 values for MGL were 4.4  U/ml for A549, 7.5 U/ml for SK-BR3, 2.4 U/ml for SKOV3, and 0.4 U/ml for MCF7 cells. The combination of doxorubicin (DOX) and MGL was more effective for A549 human lung cancer growth inhibition than either agent alone in vitro and in vivo. MGL reduced the EC50 of doxorubicin from 35.9 μg/mL t o 0.01–0.265 μg/mL. The growth inhibitory effect of DOX +&th...
Source: Investigational New Drugs - June 15, 2018 Category: Drugs & Pharmacology Source Type: research

Survival and tolerance to sorafenib in Child-Pugh B patients with hepatocellular carcinoma: a prospective study
SummarySorafenib has been widely used to treat unresectable hepatocellular carcinoma (HCC) but most studies have been done in Child-Pugh A (CP-A) patients with well-preserved liver function. We evaluated the overall survival (OS) and tolerance to sorafenib in a large cohort of Child-Pugh B (CP-B) HCC patients as compared to CP-A HCC patients. We prospectively studied 130 patients with advanced HCC who started sorafenib between January 2011 and December 2015. Patients were classified as CP-A (n = 65) or CP-B (n = 65). The average OS for all 130 patients was 10 months. CP-A patients had a med...
Source: Investigational New Drugs - June 13, 2018 Category: Drugs & Pharmacology Source Type: research

Phase II study of DFP-10917, a deoxycytidine analog, given by 14-day continuous intravenous infusion for chemotherapy-refractory advanced colorectal cancer
SummaryBackground DFP-10917 is a cytotoxic deoxycytidine analogue that causes DNA fragmentation, G2/M –phase arrest, and apoptosis. This agent has been shown to have antitumor activity against colorectal cancer (CRC) in preclinical studies and to be tolerable in patients. The purpose of our phase II trial was to evaluate the safety, efficacy and pharmacogenomics of DFP-10917 as well as DNA damage studies in patients with advanced CRC refractory to cytotoxic chemotherapy.Methods In this single-arm, Simon two-stage, phase II trial, patients with chemotherapy-refractory advanced CRC received 2.0  mg/m2/day DFP-1091...
Source: Investigational New Drugs - June 13, 2018 Category: Drugs & Pharmacology Source Type: research

A phase Ib study of sonidegib (LDE225), an oral small molecule inhibitor of smoothened or Hedgehog pathway, in combination with docetaxel in triple negative advanced breast cancer patients: GEICAM/2012 –12 (EDALINE) study
SummaryUp-regulation of the Hedgehog (Hh) pathway is implicated in the genesis of a wide range of tumors including triple negative breast cancer (TNBC). Sonidegib is a potent and selective oral inhibitor of Smo, a key component of the Hh signaling pathway. We designed a phase I clinical study to explore the combination of sonidegib plus docetaxel (fixed dose at 75  mg/m2) in advanced TNBC patients. The primary objective was to ascertain the combination ’s maximum tolerated dose and the recommended phase II dose (RP2D), based on dose limiting toxicities (DLTs) in the first 2 cycles. A standard “3&thins...
Source: Investigational New Drugs - June 9, 2018 Category: Drugs & Pharmacology Source Type: research

The poly (ADP-ribose) polymerase inhibitor rucaparib suppresses proliferation and serves as an effective radiosensitizer in cervical cancer
Conclusions Rucaparib exerts significant anti-proliferative effects and can serve as an effective radiosensitizer in cervical cancer, suggesting its candidacy in cervical cancer treatment and worthiness for further investigation. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 6, 2018 Category: Drugs & Pharmacology Source Type: research

Preclinical study of the antitumor effect of sphingosine-1-phosphate receptor 1 antibody (S1PR 1 -antibody) against human breast cancer cells
In this study, we evaluated whether a monoclonal antibody against S1PR1 (S1PR1-antibody) could impose any effect on cell growth of human breast cancer SK-BR-3 and MDA-MB-231 cells. The S1PR1-antibody exhibited cytostatic effect against both cell lines at the concentration of 4000  ng/mL. Co-administration of 4000 ng/mL of the S1PR1-antibody not only potentiated the cytotoxicity of carboplatin towards the MDA-MB-231 cells but also increased the anti-proliferative effect of S1P towards the SK-BR-3 cells. Furthermore, we showed that co-administration of S1P did not sensitize the SK-BR-3 and MDA-MB-231 cells towards ...
Source: Investigational New Drugs - June 2, 2018 Category: Drugs & Pharmacology Source Type: research

Hepatic safety analysis of trabectedin: results of a pharmacokinetic study with trabectedin in patients with hepatic impairment and experience from a phase 3 clinical trial
Conclusion Trabectedin treatment of patients with HI results in higher plasma exposures. Hepatotoxicity in patients with normal liver function can be effectively addressed through dose reductions and delays. (Source: Investigational New Drugs)
Source: Investigational New Drugs - May 11, 2018 Category: Drugs & Pharmacology Source Type: research

Translational PK-PD modeling analysis of MCLA-128, a HER2/HER3 bispecific monoclonal antibody, to predict clinical efficacious exposure and dose
Conclusions This analysis predicts that a flat dose of 10 to 480  mg q3wk is suitable as starting dose for a First-in-Human study with MCLA-128. Flat doses ≥360 mg q3wk are expected to be efficacious in human, based on receptor occupancies and PK-PD model simulations. (Source: Investigational New Drugs)
Source: Investigational New Drugs - May 5, 2018 Category: Drugs & Pharmacology Source Type: research

A multicentre, open-label phase II study of I rinotecan, capecitabine ( X eloda ®), and O xaliplatin (IXO) as first-line treatment in patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma
Conclusion mIXO demonstrates promising ORR, PFS, OS, and acceptable toxicity compared to standard triplet regimens. IXO should be evaluated in phase III trials. (Source: Investigational New Drugs)
Source: Investigational New Drugs - May 4, 2018 Category: Drugs & Pharmacology Source Type: research