Ubiquitin-specific protease 7 is a druggable target that is essential for pancreatic cancer growth and chemoresistance
SummaryPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, and most patients die within one year after diagnosis. This cancer is resistant to almost all current therapies, so there is an urgent need to identify novel druggable targets. Ubiquitin-specific protease 7 (USP7) is a deubiquitinase that functions in carcinogenesis, but its role in PDAC is unknown. Our experiments indicated that several subtypes of PDAC cells are sensitive to USP7 inhibition. In particular, pharmaceutical inhibition of USP7 by the small molecule P22077 attenuated PDAC cell growth and induced cell deathin vitro andin vivo. Ph...
Source: Investigational New Drugs - October 21, 2020 Category: Drugs & Pharmacology Source Type: research

Translational approach from preclinical to clinical: comparison of dose finding methods of a new Bcl2 inhibitor using PK-PD modeling and interspecies extrapolation
SummaryThe attrition rate of anticancer drugs during the clinical development remains very high. Interspecies extrapolation of anticancer drug pharmacodynamics (PD) could help to bridge the gap between preclinical and clinical settings and to improve drug development. Indeed, when combined with a physiologically-based-pharmacokinetics (PBPK) approach, PD interspecies extrapolation could be a powerful tool for predicting drug behavior in clinical trials. The present study aimed to explore this field for anticipating the clinical efficacy of a new Bcl-2 inhibitor, S 55746, for which dose ranging studies in xenografted mice a...
Source: Investigational New Drugs - October 21, 2020 Category: Drugs & Pharmacology Source Type: research

ABCG2 C421A polymorphisms affect exposure of the epidermal growth factor receptor inhibitor gefitinib
AbstractATP-binding castle protein G2 (ABCG2) is thought to inhibit the activities of certain gefitinib transporters, thereby affecting drug pharmacokinetics. The C421A polymorphism affects the function and expression of ABCG2 on the cell membrane. Previous studies have shown that proton-pump inhibitors (PPIs) inhibit gefitinib absorption, as well as the function of ABCG2. We evaluated the plasma concentrations of gefitinib in patients with and without the ABCG2 C421A polymorphism, who were or were not taking PPIs. In total, 61 patients with advanced epidermal-growth-factor-positive non-small-cell lung cancer were enrolled...
Source: Investigational New Drugs - October 21, 2020 Category: Drugs & Pharmacology Source Type: research

Real-world assessment of afatinib for patients with EGFR -positive non-small cell lung cancer
Conclusions Afatinib is effective for patients with NSCLC harboring commonEGFR mutations irrespective of their clinicopathological backgrounds. A direct comparison of afatinib and osimertinib in treatment-na ïve patients is warranted to determine the optimal standard of care. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 21, 2020 Category: Drugs & Pharmacology Source Type: research

A phase 1 study of PF-06840003, an oral indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor in patients with recurrent malignant glioma
SummaryBackground PF-06840003 is a highly selective indoleamine 2, 3-dioxygenase (IDO1) inhibitor with antitumor effects in preclinical models. This first-in-human phase 1 study evaluated safety, pharmacokinetics/pharmacodynamics, and preliminary efficacy in recurrent malignant glioma to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D).Methods Patients (N = 17) received oral PF-06840003 in four dose-escalation groups: 125 mg once-daily (QD;n = 2); 250 mg QD (n = 4); 250 mg twice-daily (BID;n = 3); 500 mg BID (n = 8). A modifi...
Source: Investigational New Drugs - October 21, 2020 Category: Drugs & Pharmacology Source Type: research

Recombinant human endostatin plus paclitaxel/nedaplatin for recurrent or metastatic advanced esophageal squamous cell carcinoma: a prospective, single-arm, open-label, phase II study
Conclusions Rh-endostatin plus paclitaxel/nedaplatin has anti-tumour activity with acceptable tolerability in patients with recurrent or metastatic advanced ESCC. Randomized controlled trial is needed to confirm the efficacy of this regimen. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 18, 2020 Category: Drugs & Pharmacology Source Type: research

Recombinant human lactoferrin carrying humanized glycosylation exhibits antileukemia selective cytotoxicity, microfilament disruption, cell cycle arrest, and apoptosis activities
In this study, recombinant human lactoferrin carrying humanized glycosylation (rhLf-h-glycan) expressed in the yeastPichia pastoris SuperMan5, which is genetically glycoengineered to efficiently produce functional humanized glycoproteins inclosing (Man)5(GlcNAc)2 Asn-linked glycans, was analyzed, inspecting its potential toxicity against cancer cells. The live-cell differential nuclear staining assay was used to quantify the rhLf-h-glycan cytotoxicity, which was examined in four human cell lines: acute lymphoblastic leukemia (ALL) CCRF-CEM, T-cell lymphoblastic lymphoma SUP-T1, cervical adenocarcinoma HeLa, and as control,...
Source: Investigational New Drugs - October 16, 2020 Category: Drugs & Pharmacology Source Type: research

The novel low molecular weight MYC antagonist MYCMI-6 inhibits proliferation and induces apoptosis in breast cancer cells
Conclusions Based on these findings, we conclude that for patients with breast cancer, anti-MYC therapy is likely to be most efficacious in patients with the basal subtype. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 14, 2020 Category: Drugs & Pharmacology Source Type: research

A phase Ib study of the highly selective MET-TKI savolitinib plus gefitinib in patients with EGFR -mutated, MET -amplified advanced non-small-cell lung cancer
The objective response rates in EGFR T790M-negative, −positive, and -unknown patients were 52% (12/23), 9% (2/23), and 40% (2/5), respectively. Savolitinib 600 mg plus gefitinib 250 mg once daily had an acceptable safety profile and d emonstrated promising antitumor activity in EGFRm, MET-amplified advanced NSCLC patients who had disease progression on EGFR-TKIs. NCT02374645, Date of registration: March 2nd 2015. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 14, 2020 Category: Drugs & Pharmacology Source Type: research

Glochidiol, a natural triterpenoid, exerts its anti-cancer effects by targeting the colchicine binding site of tubulin
This study aimed to investigate the anti-lung cancer effects of glochidiol in HCC-44 cellsin vitro andin vivo. In the present study, glochidiol was found to have potent antiproliferative activity against lung cancer cell lines NCI-H2087, HOP-62, NCI-H520, HCC-44, HARA, EPLC-272H, NCI-H3122, COR-L105 and Calu-6 with IC50 values of 4.12  µM, 2.01 µM, 7.53 µM, 1.62 µM, 4.79 µM, 7.69 µM, 2.36 µM, 6.07 µM and 2.10 µM, respectively.In vivo, glochidiol was found to effectively inhibit lung cancer HCC-44 xenograft tumor growth in nud...
Source: Investigational New Drugs - October 6, 2020 Category: Drugs & Pharmacology Source Type: research

Novel Bacillus strains from the human gut exert anticancer effects on a broad range of malignancy types
In this study, we isolated four bacterial strains, BY38, BY40, BY43 and BY45, from the fecal specimens of healthy individuals and cancer patients. The treatment of cancer cells with the products of these cultured bacteria induced significant inhibitory effects on the proliferation of ovarian cancer cells and colorectal cancer cells in a dose-dependent manner. A phylogenetic analysis showed that the four anticancer strains belong to the genusBacillus, and flow cytometry assays indicated that the inhibitory effects might be achieved through the induction of cell apoptosis. These results suggest that these bacteria could be n...
Source: Investigational New Drugs - September 16, 2020 Category: Drugs & Pharmacology Source Type: research

Intratumoral submicron particle docetaxel inhibits syngeneic Renca renal cancer growth and increases CD4+, CD8+, and Treg levels in peripheral blood
In this study, the Renca syngeneic murine xenograft model of renal cancer was used to evaluate the effects of intratumoral (IT) submicron particle docetaxel (NanoDoce ®) on tumor growth and immunomodulation. Tumor volume (TV) was compared to controls, including intravenous (IV) chemotherapy. Flow cytometry of peripheral bloods and tumors was used to evaluate immune cell populations. Groups of animals were inoculated with a second Renca tumor at a site distant fr om the primary tumor. IT NanoDoce significantly reduced primary TV and reduced the growth rates of untreated secondary tumors. CD4+, CD8+ and Treg populations ...
Source: Investigational New Drugs - September 16, 2020 Category: Drugs & Pharmacology Source Type: research

A phase 1 study of nevanimibe HCl, a novel adrenal-specific sterol O-acyltransferase 1 (SOAT1) inhibitor, in adrenocortical carcinoma
Conclusions This study demonstrated the safety of nevanimibe at doses of up to ~6000  mg BID. As the total number of tablets required to achieve an MTD exceeded practical administration limits, a maximumfeasible dose was defined. Given that the expected exposure levels necessary for an apoptotic effect could not be achieved, the current formulation of nevanimibe had limited efficacy in patients with advanced ACC. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 16, 2020 Category: Drugs & Pharmacology Source Type: research

A phase 1 study evaluating safety and pharmacokinetics of losatuxizumab vedotin (ABBV-221), an anti-EGFR antibody-drug conjugate carrying monomethyl auristatin E, in patients with solid tumors likely to overexpress EGFR
SummaryLosatuxizumab vedotin (formerly ABBV-221) is a second-generation antibody-drug conjugate targeting epidermal growth factor receptor (EGFR). In this multicenter phase 1 study, eligible patients with EGFR-dependent solid tumors received losatuxizumab vedotin (3  + 3 design) intravenously at starting dose of 0.3 mg/kg over 3 h per 21-day cycle, with alternate dosing schedules utilized (2 weeks on/1 week off or weekly) to mitigate infusion reactions. Forty-five patients received ≥1 doses of losatuxizumab vedotin (13 colon, 6 non-small cell lung can cer, 5 head and neck [HNC], 5 gliob...
Source: Investigational New Drugs - September 16, 2020 Category: Drugs & Pharmacology Source Type: research

Phase II trial of SM-88, a cancer metabolism based therapy, in non-metastatic biochemical recurrent prostate cancer
SummaryBackground Androgen deprivation therapy (ADT) is a standard treatment for high-risk biochemically-recurrent, non-metastatic prostate cancer (BRPC) but is not curative and associated with toxicity. Racemetyrosine (SM-88) is an amino-acid analogue used with methoxsalen, phenytoin, and sirolimus (MPS) to enhance SM-88 activity.Method A phase 1b/2, open-label trial in BRPC and rising PSA. Patients were given daily SM-88 (230  mg BID), methoxsalen (10 mg), phenytoin (50 mg), and sirolimus (0.5 mg)). Outcome measures included changes in PSA, circulating tumor cells (CTCs) and imaging.Results 34 subject...
Source: Investigational New Drugs - September 12, 2020 Category: Drugs & Pharmacology Source Type: research

Phase 1 study of 2 high dose intensity schedules of the pan-Notch inhibitor crenigacestat (LY3039478) in combination with prednisone in patients with advanced or metastatic cancer
Conclusions This study demonstrated the potential use of prednisone to reduce gastrointestinal (GI) toxicities of a Notch inhibitor without affecting its PK. The safety profile observed was consistent with Notch pathway inhibitors, and the maximum tolerated dose was 75 mg TIW and 100 mg BIW in F1 and F2, respectively. ClinicalTrials.gov: NCT01695005. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 10, 2020 Category: Drugs & Pharmacology Source Type: research

A novel LRRFIP1-ALK fusion in inflammatory myofibroblastic tumor of hip and response to crizotinib
This report expands the list of gene fusions in IMTs and highlights a new target for treatment. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 10, 2020 Category: Drugs & Pharmacology Source Type: research

Pancreatic cancer drug-sensitivity predicted by synergy of p53-Activator Wnt Inhibitor-2 (PAWI-2) and protein biomarker expression
SummaryToday, pancreatic cancer (PC) is a major health problem in the United States. It remains a challenge to develop efficacious clinically useful PC therapies. New avenues, based on translational approaches and innovative validated biomarkers could be a preclinical option to evaluate PC drug candidates or drug combinations before clinical trials. Herein, we describe evaluation of combination therapies by incorporating a novel pathway modulator,p53-ActivatorWntInhibitor-2 (PAWI-2) with other FDA-approved cancer drugs that have been used in PC clinical trials. PAWI-2 is a potent inhibitor of drug-resistant PC cells that h...
Source: Investigational New Drugs - September 10, 2020 Category: Drugs & Pharmacology Source Type: research

Mitogen-activated protein kinases are involved in cucurbitacin D-induced antitumor effects on adult T-cell leukemia cells
In this study, we investigated the effects of mitogen-activated protein kinase (MAPK) signaling inhibitors on CuD-induced cell death in peripheral blood lymphocytes (PBLs) isolated from ATL/acute lymphoblastic leukemia (ALL) patients and two human leukemia cell lines (MT-1 and MT-4). PBLs were isolated from an ATL/ALL patient as well as from a healthy donor. Cell surface markers were examined using flow cytometry. Serum cytokine levels were estimated using LEGENDplex or analyzed at the Center for Clinical and Translational Research of Kyushu University Hospital. Cell proliferation was assessed using the Cell Titer-Glo lumi...
Source: Investigational New Drugs - September 9, 2020 Category: Drugs & Pharmacology Source Type: research

Immunologic and tumor responses of pegilodecakin with 5-FU/LV and oxaliplatin (FOLFOX) in pancreatic ductal adenocarcinoma (PDAC)
Conclusions Pegilodecakin+FOLFOX had an acceptable tolerability profile in PDAC, with no substantial irAEs seen, and promising efficacy with the combination yielding a 2-year OS of 24% (95% CI 10 –42). These data led to the phase 3 study with pegilodecakin+FOLFOX as second-line therapy of PDAC (SEQUOIA). (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 9, 2020 Category: Drugs & Pharmacology Source Type: research

Correction to: Phase 1 dose-escalation study of a novel oral PI3K/mTOR dual inhibitor, LY3023414, in patients with cancer
The article Phase 1 dose-escalation study of a novel oral PI3K/mTOR dual inhibitor, LY3023414, in patients with cancer, written by Shunsuke Kondo, Masaomi Tajimi, Tomohiko Funai, Koichi Inoue, Hiroya Asou, Vinay Kumar Ranka, Volker Wacheck, Toshihiko Doi, was originally published electronically on the publisher ’s internet portal on 23 June 2020 without open access. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 6, 2020 Category: Drugs & Pharmacology Source Type: research

The anti-malaria agent artesunate exhibits cytotoxic effects in primary effusion lymphoma
SummaryPrimary effusion lymphoma (PEL), caused by Kaposi ’s sarcoma-associated herpesvirus (KSHV), presents as a lymphomatous effusion in body cavities and has a poor prognosis. The anti-malaria drug, artesunate, possesses anti-neoplastic potential. Therefore, we aimed to investigate its effect on KSHV-infected PEL cell lines. Artesunate inhibited cell growth and viability of PEL cells, but its effect on peripheral blood mononuclear cells was less pronounced. Artesunate induced G1 phase arrest by downregulating cyclin D1/D2, CDK2/6 and c-Myc. Artesunate increased reactive oxygen species and DNA damage, but did not af...
Source: Investigational New Drugs - September 2, 2020 Category: Drugs & Pharmacology Source Type: research

Novel [l,2,4]triazolo[3,4- a ]isoquinoline chalcones as new chemotherapeutic agents: Block IAP tyrosine kinase domain and induce both intrinsic and extrinsic pathways of apoptosis
SummaryTwo novel chemotherapeutic chalcones were synthesized and their structures were confirmed by different spectral tools. Theoretical studies such as molecular modeling were done to detect the mechanism of action of these compounds.In vitro cytotoxicity showed a strong effect against all tested cell lines (MCF7, A459, HepG2, and HCT116), and low toxic effect against normal human melanocytes (HFB4). The lung carcinoma cell line was chosen for further molecular studies. Real-time PCR demonstrated that the two compounds upregulated gene expression of (BAX, p53, casp-3, casp-8, casp-9) genes and decreased the expression of...
Source: Investigational New Drugs - August 27, 2020 Category: Drugs & Pharmacology Source Type: research

Serum concentration of the CKD4/6 inhibitor abemaciclib, but not of creatinine, strongly predicts hematological adverse events in patients with breast cancer: a preliminary report
Conclusions Abemaciclib concentrations are associated with neutropenia and thrombocytopenia. However, increase in serum creatinine levels may not be a useful predictor for estimating abemaciclib pharmacokinetics and hematological toxicity. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 26, 2020 Category: Drugs & Pharmacology Source Type: research

Atorvastatin in combination with radiotherapy and temozolomide for glioblastoma: a prospective phase II study
This study evaluated the efficacy of atorvastatin in combination with standard therapy in patients with glioblastoma. In this prospective, open-label, single-arm, phase II study, patients were treated with atorvastatin in combination with the standard glioblastoma therapy comprising radiotherapy and temozolomide. The primary endpoint was progression-free survival (PFS) at 6  months (PFS-6). Among 36 patients enrolled from January 2014 to January 2017, the median age was 52 (20–69) years; 22% of the patients were aged ≥60 years, and 62% were male. Patients received atorvastatin for a median duration of 6....
Source: Investigational New Drugs - August 26, 2020 Category: Drugs & Pharmacology Source Type: research

Efficacy of the eribulin, pertuzumab, and trastuzumab combination therapy for human epidermal growth factor receptor 2 –positive advanced or metastatic breast cancer: a multicenter, single arm, phase II study (JBCRG-M03 study)
Conclusions In patients with HER2-positive AMBC, eribulin, pertuzumab, and trastuzumab combination therapy exhibited substantial antitumor activity with an acceptable safety profile. Hence, we have started a randomized phase III study comparing eribulin and a taxane in combination with pertuzumab and trastuzumab for the treatment of HER2-positive AMBC.Trial registration ID: UMIN-CTR: UMIN000012232. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 23, 2020 Category: Drugs & Pharmacology Source Type: research

Crizotinib induced antitumor activity and synergized with chemotherapy and hormonal drugs in breast cancer cells via downregulating MET and estrogen receptor levels
In this study, the anticancer effects of crizotinib on breast cancer cells were investigated in vitro along with the molecular mechanisms associated with these effects. Besides, the antiproliferative effects of crizotinib in combination with chemotherapy, hormonal drugs, and targeted agents were examined. Results showed that crizotinib produced dose-dependent antiproliferative effects in BT-474 and SK-BR-3 breast cancer cells with IC50 values of 1.7  μM and 5.2 μM, respectively. Crizotinib inhibited colony formation of BT-474 cells at low micromolar concentrations (1–5 μM). Immunofluorescence ...
Source: Investigational New Drugs - August 23, 2020 Category: Drugs & Pharmacology Source Type: research

Effects of zinc porphyrin and zinc phthalocyanine derivatives in photodynamic anticancer therapy under different partial pressures of oxygen in vitro
In conclusion, our observations suggest that PDT can be effective even in hypoxic conditions if a suitable sensitizer is chosen, such as ZnPcS2, which can inhibit mitochondrial respiration. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 23, 2020 Category: Drugs & Pharmacology Source Type: research

Erlotinib and bevacizumab in elderly patients ≥75 years old with non-small cell lung cancer harboring epidermal growth factor receptor mutations
The objective response rate was 88.0% [95% CI: 74.0%–99.0%], and the disease c ontrol rate was 100% [95% CI: 88.7%–100%]. Grade 3 or higher adverse events occurred in 12 patients (48.0%), and rash and nausea were the most common. Grade 3 or higher bevacizumab-related toxicities occurred in 4 (16.0%) patients, including proteinuria (n = 2), gastrointestinal perforation (n = 1) and pneumothorax (n = 1). A dose reduction of erlotinib and cessation of bevacizumab was required in 16 (64.0%) and 18 patients (72.0%), respectively. Erlotinib and bevacizumab combination therapy ...
Source: Investigational New Drugs - August 16, 2020 Category: Drugs & Pharmacology Source Type: research

Phase I/II study of erlotinib plus S-1 for patients with previously treated non-small cell lung cancer: Thoracic Oncology Research Group (TORG) 0808/0913
Conclusion The combination therapy of erlotinib plus S-1 was not feasible in the EGFR wild-type NSCLC at least and early stopped. Trial registration: UMIN-CTR Identifier: 000003421 (2010/03/31, phase I), 000003422 (2010/03/31, Phase II). (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 14, 2020 Category: Drugs & Pharmacology Source Type: research

Development of a carrier system containing hyaluronic acid and protamine for siRNA delivery in the treatment of melanoma
SummaryThe use of small interfering RNA (siRNA) in melanoma treatment remains limited owing to its biological properties. Herein, we developed a carrier system containing hyaluronic acid and protamine for siRNA delivery. Considering zeta potential and particle size as standards, the ratio of each component in liposome nanoparticles prepared was screened using the control variable method, and siRNA cationic liposome nanoparticles were prepared based on the optimal results obtained. The encapsulation rate of the cationic liposome nanoparticles was measured, and particle morphology was observed. B16F10 cells were treated with...
Source: Investigational New Drugs - August 12, 2020 Category: Drugs & Pharmacology Source Type: research

Atezolizumab plus carboplatin and etoposide in small cell lung cancer patients previously treated with platinum-based chemotherapy
SummaryAlthough immune checkpoint inhibitors have improved the survival of small cell lung cancer (SCLC) patients, their efficacy in SCLC patients who relapsed after systemic chemotherapy is unclear. This retrospective study aimed to investigate the utility of treatment with atezolizumab plus carboplatin and etoposide in SCLC patients previously treated with platinum-based chemotherapy. We retrospectively screened consecutive eight SCLC patients who received atezolizumab plus carboplatin and etoposide after platinum-based chemotherapy. We evaluated the efficacy of this treatment and its association with programmed cell dea...
Source: Investigational New Drugs - August 10, 2020 Category: Drugs & Pharmacology Source Type: research

Analysis and identification of novel biomarkers involved in neuroblastoma via integrated bioinformatics
This study distinguished hub genes and related signaling pathways that can potentially serve as diagnostic indicators and therapeutic biomarkers for NB, thereby improving understanding of the molecular mechanisms involved in NB. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 7, 2020 Category: Drugs & Pharmacology Source Type: research

Dual-function chimeric antigen receptor T cells targeting c-Met and PD-1 exhibit potent anti-tumor efficacy in solid tumors
Conclusion These results confirm that the novel dual-function CAR-T cells exhibit stronger anti-tumor activity against solid tumors than traditional single-target CAR-T cells and present a new approach that enhance the activity of CAR-T cells in solid tumors. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 7, 2020 Category: Drugs & Pharmacology Source Type: research

A phase I study of intraperitoneal paclitaxel combined with gemcitabine plus nab-paclitaxel for pancreatic cancer with peritoneal metastasis
Conclusions. Ip PTX combined with GnP was feasible and potentially effective in pancreatic cancer with peritoneal metastasis as a first-line treatment deserved further evaluations. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 7, 2020 Category: Drugs & Pharmacology Source Type: research

Glioma progression is suppressed by Naringenin and APO2L combination therapy via the activation of apoptosis in vitro and in vivo
SummaryNaringenin (NG) is a natural antioxidant flavonoid which is isolated from citrus fruits, and has been reported to inhibit colon cancer proliferation. However, the effects of NG treatment on glioma remain to be elucidated. The present study aimed to explore the effects of NG on glioma in vitro and in vivo. Also, the interactions between NG and APO2 ligand (APO2L; also known as tumor necrosis factor-related apoptosis-inducing ligand) were investigated in glioma. A synergistic effect of NG and APO2L combination on apoptotic induction was observed, though glioma cells were insensitive to APO2L alone. After NG treatment,...
Source: Investigational New Drugs - August 6, 2020 Category: Drugs & Pharmacology Source Type: research

B7-H6 as an efficient target for T cell-induced cytotoxicity in haematologic malignant cells
In this study, we examined the expression of new B7 family members B7-H4, B7-H5, B7-H6, and B7-H7 in human haematological tumour cells. Furthermore, we explored whether B7-H6 is an efficient target for T cell-induced cytotoxicity in haematologic malignant cells. We determined the capability of T cells armed with the bispecific antibody anti-CD3  × anti-B7-H6 (B7-H6Bi-Ab) to target haematological tumours in K562, Thp-1, Daudi, Jurkat, and U266 cells. Compared with their T cell counterparts, B7-H6Bi-Ab-armed T cells demonstrated significant cytotoxicity induction in B7-H6+ haematological tumour cells, acc...
Source: Investigational New Drugs - August 6, 2020 Category: Drugs & Pharmacology Source Type: research

Real-world systemic sequential therapy with sorafenib and regorafenib for advanced hepatocellular carcinoma: a multicenter retrospective study in Korea
Conclusions This real-word regorafenib study showed comparable effectiveness and safety to the RESORCE trial. Regorafenib improves the prognosis of patients with prolonged TTP during previous sorafenib therapy. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 3, 2020 Category: Drugs & Pharmacology Source Type: research

Therapeutic efficacy and imaging assessment of the HER2-targeting chemotherapy drug Z HER2:V2 -pemetrexed in lung adenocarcinoma Xenografts
SummaryChemotherapy has always been the first therapeutic option for patients with advanced non-small cell lung cancer (NSCLC) with untreatable oncogenic mutations. However, chemotherapy has demonstrated limited success and is associated with severe side effects. This research aimed to investigate the antitumor efficacy and cytotoxic safety of the conjugate ZHER2:V2-pemetrexed, a novel targeted chemotherapeutic drug. In this context, human epidermal growth factor receptor 2 (HER2)  + A549 lung xenografts were treated using ZHER2:V2-pemetrexed, pemetrexed or physiological saline. Therapeutic efficacy was monit...
Source: Investigational New Drugs - July 7, 2020 Category: Drugs & Pharmacology Source Type: research

Synthesis and cellular effects of novel 1,3,5-triazine derivatives in DLD and Ht-29 human colon cancer cell lines
This study provides new information on the cellular effects of 1,3,5-triazine nitrogen mustards with different peptide groups in DLD and Ht-29 human colon cancer cell lines. A novel series of 2,4,6-trisubstituted 1,3,5-triazine derivatives bearing 2-chloroethyl and oligopeptide moieties was designed and synthesized. The most cytotoxic derivative was triazine with an Ala-Ala-OMe substituent on the ring (compound7b). This compound induced time- and dose-dependent cytotoxicity in the DLD-1 and HT-29 colon cancer cell lines. The triazine derivative furthermore induced apoptosis through intracellular signaling pathway attenuati...
Source: Investigational New Drugs - July 7, 2020 Category: Drugs & Pharmacology Source Type: research

A phase 1 study of the MDM2 antagonist RO6839921, a pegylated prodrug of idasanutlin, in patients with advanced solid tumors
Conclusions RO6839921 showed reduced pharmacokinetic exposure variability and a safety profile comparable with that of  oral idasanutlin. Although this study indicated that RO6839921 could be administered to patients, the results did not provide sufficient differentiation or improvement in the biologic or safety profile compared with oral idasanutlin to support continued development. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 7, 2020 Category: Drugs & Pharmacology Source Type: research

A phase Ib study of a PI3Kinase inhibitor BKM120 in combination with panitumumab in patients with KRAS wild-type advanced colorectal cancer
Conclusion Panitumumab (6  mg/kg iv q 2 weeks) with BKM120 60 mg given 5 out of 7 days per week was declared the RP2D. Toxicities including fatigue, rash and mucositis. There was little evidence of activity in this biomarker unselected cohort. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 7, 2020 Category: Drugs & Pharmacology Source Type: research

Matteucinol, isolated from Miconia chamissois , induces apoptosis in human glioblastoma lines via the intrinsic pathway and inhibits angiogenesis and tumor growth in vivo
This study was conducted to investigate the antitumor potential (in vitro and in vivo) ofMiconia chamissois Naudin for treating glioblastomas. We investigated the cytotoxicity of the chloroform partition and its sub-fraction in glioblastoma cell lines (GAMG and U251MG) and one normal cell line of astrocytes. The fraction showed cytotoxicity and was selective for tumor cells. Characterization of this fraction revealed a single compound, Matteucinol, which was first identified in the speciesM. chamissois. Matteucinol promoted cell death via intrinsic apoptosis in the adult glioblastoma lines. In addition, Matteucinol signifi...
Source: Investigational New Drugs - July 7, 2020 Category: Drugs & Pharmacology Source Type: research

Extrahepatic metabolism of ibrutinib
SummaryIbrutinib is a first-in-class Bruton ’s kinase inhibitor used in the treatment of multiple lymphomas. In addition to CYP3A4-mediated metabolism, glutathione conjugation can be observed. Subsequently, metabolism of the conjugates and finally their excretion in feces and urine occurs. These metabolites, however, can reach substantial c oncentrations in human subjects, especially when CYP3A4 is inhibited. Ibrutinib has unexplained nephrotoxicity and high metabolite concentrations are also found in kidneys of Cyp3a knockout mice. Here, a mechanism is proposed where the intermediate cysteine metabolite is bioactiva...
Source: Investigational New Drugs - July 3, 2020 Category: Drugs & Pharmacology Source Type: research

Mitomycin C plus cisplatin for systemic treatment of recurrent BRCA1 -associated ovarian cancer
Conclusions Mitomycin C plus cisplatin shows promising activity in recurrentBRCA1-driven ovarian cancer. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 25, 2020 Category: Drugs & Pharmacology Source Type: research

Correction to: Clinical and radiation dose-volume factors related to pneumonitis after treatment with radiation and durvalumab in locally advanced non-small cell lung cancer
Corrections are needed to the original version of this article. In Table 2, the “Odds ratio” of the variables “Lower lobe vs. Upper lobe” and “≥26 vs.
Source: Investigational New Drugs - June 25, 2020 Category: Drugs & Pharmacology Source Type: research

Phase 1 dose-escalation study of a novel oral PI3K/mTOR dual inhibitor, LY3023414, in patients with cancer
We report results of a 3  + 3 dose-escalation Phase 1 study for twice-daily (BID) dosing of LY3023414 monotherapy in Japanese patients with advanced malignancies. The primary objective was to evaluate tolerability and safety of LY3023414. Secondary objectives were to evaluate pharmacokinetics and to explore antitumor ac tivity. A total of 12 patients were enrolled and received 150 mg (n = 3) or 200 mg (n = 9) LY3023414 BID. Dose-limiting toxicities were only reported at 200 mg LY3023414 for 2 patients with Grade 3 stomatitis. Common treatment-related adverse events (...
Source: Investigational New Drugs - June 22, 2020 Category: Drugs & Pharmacology Source Type: research

Correction to: Phase I dose escalation study of BI 836826 (CD37 antibody) in patients with relapsed or refractory B cell non-Hodgkin lymphoma
The original version of this article unfortunately contained an error. In the Conflict of interest statement, Anne-Marie Quinson is described as declaring no conflict of interest. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 22, 2020 Category: Drugs & Pharmacology Source Type: research

Correction to: The old CEACAMs find their new role in tumor immunotherapy
Correction is needed to the original version of this article. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 21, 2020 Category: Drugs & Pharmacology Source Type: research

The safety and tolerability of epacadostat alone and in combination with pembrolizumab in patients with advanced solid tumors: results from a first-in-Japanese phase I study (KEYNOTE-434)
ConclusionEpacadostat in combination with pembrolizumab was generally safe and well tolerated among Japanese patients with advanced solid tumors.Clinical trial registration NCT02862457. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 19, 2020 Category: Drugs & Pharmacology Source Type: research