A phase I study of AT-101, a BH3 mimetic, in combination with paclitaxel and carboplatin in solid tumors
Conclusion The combination of AT-101 at 40  mg every 12 h on days 1, 2 and 3 combined with paclitaxel and carboplatin was safe and tolerable. Based on the modest clinical efficacy seen in this trial, this combination will not be further investigated. Clinical Trial Registration: NCT00891072, CTEP#: 8016. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 6, 2019 Category: Drugs & Pharmacology Source Type: research

Phase I study of the anti-endothelin B receptor antibody-drug conjugate DEDN6526A in patients with metastatic or unresectable cutaneous, mucosal, or uveal melanoma
Conclusion DEDN6526A administered at the RP2D of 2.4  mg/kg q3w had an acceptable safety profile and showed evidence of anti-tumor activity in patients with cutaneous, mucosal, and uveal melanoma. ClinicalTrials.gov identifier: NCT01522664. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 5, 2019 Category: Drugs & Pharmacology Source Type: research

Efficacy of immune checkpoint blockade in MUTYH -associated hereditary colorectal cancer
SummaryColorectal carcinomas (CRCs) caused by hereditary biallelicMUTYH gene mutations are characterized by elevated mutation load and high lymphocyte infiltration. Given that these tumor features are associated with the response to immune checkpoint inhibitors, we administered nivolumab to a CRC patient who carried two inactiveMUTYH alleles (p.Y179C and p.G396D) and previously experienced failure of chemotherapy. This experimental treatment resulted in a pronounced tumor response. We further compared tumor lymphocyte infiltration inMUTYH-associated (n = 3), high-level microsatellite instability (MSI-H,n&thin...
Source: Investigational New Drugs - August 3, 2019 Category: Drugs & Pharmacology Source Type: research

Ibrutinib as a potential therapeutic option for HER2 overexpressing breast cancer – the role of STAT3 and p21
In this study, we have performed a kinome array analysis of ibrutinib treatment in two HER2 overexpressing breast ca ncer cell lines. Our analysis shows that ibrutinib induces changes in nuclear morphology and causes apoptosis via caspase-dependent extrinsic apoptosis pathway with the activation of caspases-8, caspase-3, and cleavage of PARP1. We further show that phosphorylated STAT3Y705 is upregulated and phosphorylated p21T145 is downregulated upon ibrutinib treatment. We propose that STAT3 upregulation is a passive response as a result of induction of DNA damage and downregulation of phosphorylated p21 is promoting cel...
Source: Investigational New Drugs - August 2, 2019 Category: Drugs & Pharmacology Source Type: research

E6201, an intravenous MEK1 inhibitor, achieves an exceptional response in BRAF V600E-mutated metastatic malignant melanoma with brain metastases
SummaryMalignant melanoma (MM) exhibits a high propensity for central nervous system dissemination with ~50% of metastatic MM patients developing brain metastases (BM). Targeted therapies and immune checkpoint inhibitors have improved overall survival for MM patients with BM. However, responses are usually of short duration and new agents that effectively penetrate the blood brain barrier (BBB) are needed. Here, we report a MM patient with BM who experienced an exceptional response to E6201, an ATP-competitive MEK1 inhibitor, on a Phase 1 study, with ongoing near-complete response and overall survival extending beyond 8 &n...
Source: Investigational New Drugs - July 13, 2019 Category: Drugs & Pharmacology Source Type: research

A phase I study of the safety and tolerability of VLX600, an Iron Chelator, in patients with refractory advanced solid tumors
Conclusion VLX600 was reasonably well tolerated and, together with preclinical data, there is support for further efforts to explore its activity as single agent and in combination with drugs or radiation. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 13, 2019 Category: Drugs & Pharmacology Source Type: research

Phase 1b study of a small molecule antagonist of human chemokine (C-C motif) receptor 2 (PF-04136309) in combination with nab-paclitaxel/gemcitabine in first-line treatment of metastatic pancreatic ductal adenocarcinoma
Conclusions PF-04136309 in combination with nab-paclitaxel plus gemcitabine had a safety profile that raises concern for synergistic pulmonary toxicity and did not show an efficacy signal above nab-paclitaxel and gemcitabine.ClinicalTrials.gov identifier: NCT02732938. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 12, 2019 Category: Drugs & Pharmacology Source Type: research

Dirty deeds done dirt cheap: sensitization of prostate cancer cells to abiraterone treatment using hydroxylated polychlorinated biphenyls
SummaryEffective targeting of androgen biosynthesis by the 17 α-hydroxylase/17,20-lyase inhibitor abiraterone prolongs survival in a variety of prostate cancer patients. However, resistance to abiraterone treatment occurs frequently and the development of new drugs supporting or complementing abiraterone therapy is urgently needed. We recently reported antipr oliferative and proapoptotic effects of hydroxylated polychlorinated biphenyls (PCBs) on various blood cell lines in vitro. Here we report the biological evaluation of the PCB28 derived OH-metabolites 3-OHCB28 or 3′-OHCB28 in prostate cancer cells. Dependi...
Source: Investigational New Drugs - July 11, 2019 Category: Drugs & Pharmacology Source Type: research

TS-1 add-on therapy in Japanese patients with triple-negative breast cancer after neoadjuvant or adjuvant chemotherapy: a feasibility study
Conclusions The 365-day cumulative rate of TS-1 administration in TNBC patients was comparable to that in gastric cancer patients despite previous chemotherapy with anthracyclines and/or taxanes. TAT was feasible for TNBC patients after standard primary therapy. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 10, 2019 Category: Drugs & Pharmacology Source Type: research

Autophagy inhibition potentiates ruxolitinib-induced apoptosis in JAK2 V617F cells
In conclusion, ruxolitinib induces autophagy in JAK2V617F cells, potentially by modulation of mTOR-, STAT- and BCL2-mediated signaling. This may lead to inhibition of apoptosis. Our results suggest that the combination of ruxolitinib with pharmacological inhibitors of autophagy, such as chloroquine, may be a promising strategy to treat patients with JAK2V617F-mutated MPNs. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 8, 2019 Category: Drugs & Pharmacology Source Type: research

Design, synthesis, and biological activity of TLR7-based compounds for chemotherapy-induced alopecia
SummaryHair loss is a common dermatosis symptom and side-effect in cancer chemotherapeutics. Imiquimod application at mid and late telogen activated the hair follicle stem cells leading to premature hair cycle entry. Based on quinoline structure, a newly synthesized compound 6b displayed proliferation activity in vitro and in vivo through branch chain replacement and triazole ring cyclization. Toll-like receptors (TLRs) are also critical mediators of the immune system, and their activation is linked to various diseases. The present study aimed to expand new agonists within co-crystallization of TLR7 (PDB code: 5GMH); howev...
Source: Investigational New Drugs - July 4, 2019 Category: Drugs & Pharmacology Source Type: research

T cell cytotoxicity toward hematologic malignancy via B7-H3 targeting
In conclusion, B7-H3Bi-Ab enhances the ability of T cells to kill hematologic tumor cells, and B7-H3 may serve as a novel target for immunotherapy against hematologic malignancy. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 3, 2019 Category: Drugs & Pharmacology Source Type: research

LncRNA differentiation antagonizing non-protein coding RNA promotes proliferation and invasion through regulating miR-135a/NLRP37 axis in pancreatic cancer
Conclusion DANCR promoted proliferation and invasion through the regulating of miR-135a / NLRP3 axis in pancreatic cancer cell. Our results suggest that DANCR may be a potential target for the therapy of pancreatic cancer. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 3, 2019 Category: Drugs & Pharmacology Source Type: research

A new BET inhibitor, 171, inhibits tumor growth through cell proliferation inhibition more than apoptosis induction
SummaryThe bromodomain and extra-terminal domain (BET) family of proteins, especially bromodomain-containing protein 4 (BRD4), has emerged as exciting anti-tumor targets due to their important roles in epigenetic regulation. Therefore, the discovery of BET inhibitors with promising anti-tumor efficacy will provide a novel approach to epigenetic anticancer therapy. Recently, we discovered the new BET inhibitor compound 171, which is derived from a polo-like kinase 1 (PLK1)-BRD4 dual inhibitor based on our previous research. Compound 171 was found to maintain BET inhibition ability without PLK1 inhibition, and there was no s...
Source: Investigational New Drugs - July 3, 2019 Category: Drugs & Pharmacology Source Type: research

In vivo and in vitro inhibition of osteosarcoma growth by the pan Bcl-2 inhibitor AT-101
SummaryOsteosarcoma (OS) is the most common primary malignant bone tumor and mainly affects children and adolescents. The OS five-year survival rate remains very low. Thus, novel therapeutic protocols for the treatment of OS are needed. Several approaches targeting deregulated signaling pathways have been proposed. The antitumoral effects of polyphenols, which are naturally occurring compounds with potent antioxidant and anti-inflammatory activity, have been investigated in different tumors. Gossypol, which is a natural polyphenolic aldehyde isolated from the seeds of the cotton plant, has been shown to exert antitumoral a...
Source: Investigational New Drugs - July 2, 2019 Category: Drugs & Pharmacology Source Type: research

Retrospective comparison of nab-paclitaxel plus ramucirumab and paclitaxel plus ramucirumab as second-line treatment for advanced gastric cancer focusing on peritoneal metastasis
Conclusion This study suggests that RAM plus nab-PTX might be a more effective treatment for peritoneal metastasis of AGC. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 2, 2019 Category: Drugs & Pharmacology Source Type: research

Xanthan gum-based hydrogel containing nanocapsules for cutaneous diphenyl diselenide delivery in melanoma therapy
SummaryThe aim of this study was to further evaluate the antitumoral effect of (PhSe)2-loaded polymeric nanocapsules (NC (PhSe)2) against a resistant melanoma cell line (SK-Mel-103) and develop a xanthan gum-based hydrogel intending the NC (PhSe)2 cutaneous application. For the in vitro evaluation, cells were incubated with free (PhSe)2 or NC (PhSe)2 (0.7 –200 μM) and after 48 h the MTT assay, propidium iodide uptake (necrosis marker) and nitrite levels were assessed. The hydrogels were developed by thickening of the NC (PhSe)2 suspension or (PhSe)2 solution with xanthan gum and characterized in terms of...
Source: Investigational New Drugs - July 2, 2019 Category: Drugs & Pharmacology Source Type: research

Dual functionality of the antimicrobial agent taurolidine which demonstrates effective anti-tumor properties in pediatric neuroblastoma
SummaryHigh-risk, relapsed and refractory neuroblastoma are associated with poor 5-years survival rates, demonstrating the need for investigational therapeutic agents to treat this disease. Taurolidine is derived from the aminosulfoacid taurine and has known anti-microbial and anti-inflammatory properties. Taurolidine has also demonstrated anti-neoplastic effects in a range of cancers, providing the rationale to investigate the activity of taurolidine against neuroblastoma in preclinical studies. We investigated the in vitro activity of taurolidine against neuroblastoma using the alamar blue cytotoxicity assay, phase-contr...
Source: Investigational New Drugs - July 2, 2019 Category: Drugs & Pharmacology Source Type: research

Targeting ROS overgeneration by N-benzyl-2-nitro-1-imidazole-acetamide as a potential therapeutic reposition approach for cancer therapy
Conclusion The current findings indicate that BZN acts as a tumor growth inhibitor and anti-angiogenic agent by ROS overgeneration, which interact with DNA causing damage and triggering apoptosis. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 1, 2019 Category: Drugs & Pharmacology Source Type: research

Vitamin K 3 thio-derivative: a novel specific apoptotic inducer in the doxorubicin-sensitive and -resistant cancer cells
In conclusion, the synthetic vitamin K3 thio-derivative (VKT-1) inhibited doxorubicin-sensitive and -resistant tumor cells by cell arrest, apoptosis induction, as well as, migration inhibition, and microtubule deterioration of U2OS-GFP- α-tubulin cells. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 29, 2019 Category: Drugs & Pharmacology Source Type: research

Evaluation of absorption, distribution, metabolism, and excretion of [ 14 C]-rucaparib, a poly(ADP-ribose) polymerase inhibitor, in patients with advanced solid tumors
SummaryRucaparib, a poly(ADP-ribose) polymerase inhibitor, is licensed for use in recurrent ovarian, fallopian tube, or primary peritoneal cancer. We characterized the absorption, distribution, metabolism, and elimination of rucaparib in 6 patients with advanced solid tumors following a single oral dose of [14C]-rucaparib 600  mg (≈140 μCi). Total radioactivity (TRA) in blood, plasma, urine, and feces was measured using liquid scintillation counting. Unchanged rucaparib concentrations in plasma were determined using validated liquid chromatography with tandem mass spectrometry. Maximum concentration (Cma...
Source: Investigational New Drugs - June 27, 2019 Category: Drugs & Pharmacology Source Type: research

Broccoli sprout supplementation in patients with advanced pancreatic cancer is difficult despite positive effects —results from the POUDER pilot study
SummaryPancreatic ductal adenocarcinoma is a highly aggressive malignancy with short survival and limited therapeutic options. Broccoli sulforaphane is a promising new treatment due to the results of recent epidemiological, experimental and patient studies. Upon approval from the ethics committee and registration atClinicalTrials.gov, 40 patients with palliative chemotherapy were placed into a placebo and treatment group in an unblinded fashion. Fifteen capsules with pulverized broccoli sprouts containing 90  mg/508 μmol sulforaphane and 180 mg/411 μmol glucoraphanin or methylcellulose were admini...
Source: Investigational New Drugs - June 27, 2019 Category: Drugs & Pharmacology Source Type: research

Tetra-substituted pyrrole derivatives act as potent activators of p53 in melanoma cells
In this study, we tested the efficacy of the previously synthesized tetra-substituted pyrrole derivatives,8  g,8  h and8i, in melanoma cell lines, and we compared the effects of the most active of these, the8i compound, with that exerted by Nutlin 3, a well-known inhibitor of p53-MDM2 interaction. The obtained results showed that8i potentiates the inhibitory effect of Nutlin 3 and the combined use of8i and Nutlin 3 triggers apoptosis and significantly impairs melanoma viability. Finally, the8i compound reduces p53-MDM2 interaction and induces p53-HSP90 complex formation, suggesting that the observed raise in p53 ...
Source: Investigational New Drugs - June 26, 2019 Category: Drugs & Pharmacology Source Type: research

A randomized phase 2 trial of the efficacy and safety of a novel topical povidone-iodine formulation for Cancer therapy-associated Paronychia
Conclusions Treatment with twice-daily topical 2% PVP-I was safe and resulted in improvement in CAP compared with control. Clinicaltrials.gov identifier: NCT03207906.https://clinicaltrials.gov/ct2/show/NCT03207906 (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 26, 2019 Category: Drugs & Pharmacology Source Type: research

Anticancer activity of a novel methylated analogue of L- mimosine against an in vitro model of human malignant melanoma
SummaryThe anticancer activity of a series of novel synthesized, hydroxypyridone-based metal chelators (analogues ofL-mimosine) was evaluated in an in vitro model of melanoma consisting of malignant melanoma (A375), non-melanoma epidermoid carcinoma (A431) and immortalized non-malignant keratinocyte (HaCaT) cells. More specifically, we have demonstrated that theL-enantiomer of a methylated analogue ofL-mimosine (compound 22) can exert a potent anticancer effect in A375 cells when compared to either A431 or HaCaT cells. Moreover, we have demonstrated that this analogue has the ability to i) promote increased generation of r...
Source: Investigational New Drugs - June 26, 2019 Category: Drugs & Pharmacology Source Type: research

Phase II trial of continuous treatment with sunitinib in patients with high-risk (BCG-refractory) non-muscle invasive bladder cancer
Conclusions In NMIBC refractory to BCG, treatment with sunitinib was safe but not associated with improved clinical outcomes. The immune effects of sunitinib deserve further investigation. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 24, 2019 Category: Drugs & Pharmacology Source Type: research

A multicenter, prospective phase II trial of gemcitabine plus axitinib in patients with renal cell carcinoma with a predominant sarcomatoid component
Conclusion GX showed promising efficacy in patients with SRCC. GX could be considered as a treatment option for patients with SRCC and should be confirmed in larger clinical trials. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 24, 2019 Category: Drugs & Pharmacology Source Type: research

A phase I dose-reduction study of apatinib combined with pemetrexed and carboplatin in untreated EGFR and ALK negative stage IV non-squamous NSCLC
Conclusion In patients with advanced non-squamous NSCLC, the feasible dose of apatinib given with standard-dose pemetrexed and carboplatin was 500  mg/day schedule 2/1. The schedule was generally well tolerated and demonstrated promising clinical benefit in NSCLC. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 24, 2019 Category: Drugs & Pharmacology Source Type: research

Cotargeting the JAK/STAT signaling pathway and histone deacetylase by ruxolitinib and vorinostat elicits synergistic effects against myeloproliferative neoplasms
SummaryThe majority of patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) harbor a gain of function mutation V617F in Janus kinase (JAK) 2. Although JAK2 inhibitors such as ruxolitinib have been shown to be clinically efficacious, the hematological toxicity and eventual drug resistance limit its use as monotherapy. Other gene mutations or dysregulation correlated with the disease phenotype and prognosis have been found to contribute to the complexity and heterogeneity of MPNs, giving rise to an increasing demand for combination therapies. Here, we combine ruxolitinib and the histone deacetylase inhibit...
Source: Investigational New Drugs - June 22, 2019 Category: Drugs & Pharmacology Source Type: research

Anticancer evaluation of a novel dithiocarbamate hybrid as the tubulin polymerization inhibitor
SummaryNovel quinoline-dithiocarbamate hybrids were synthesized and designed by the molecular hybridization strategy. All these derivatives were evaluated for their antiproliferative activity against three selected cancer cell lines (MGC-803, HepG-2 and PC-3). Among them, compound10c displayed the best antiproliferative activity against PC-3 cells with an IC50 value of 0.43  μM. Celluar mechanisms investigated that compound10c could inhibit the migration against PC-3 cells by regulation the expression levels of E-cadherin and N-cadherin. Compound10c induced morphological changes of PC-3 cells and regulated apoptosi...
Source: Investigational New Drugs - June 10, 2019 Category: Drugs & Pharmacology Source Type: research

Negative impact of malignant effusion on osimertinib treatment for non-small cell lung cancer harboring EGFR mutation
Summary3rd-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, have reasonable efficacy in non –small-cell lung cancers (NSCLC) withEGFR mutations. However, the efficacy of osimertinib in NSCLC patients with fluids, such as pleural, pericardial and abdominal effusions, is unclear. We evaluated the efficacy of osimertinib in this specific setting. NSCLC patients harboringEGFR T790  M mutations who experienced progressive disease after first EGFR-TKI treatment and started osimertinib treatment between April 2016 and August 2018 were retrospectively screened. I...
Source: Investigational New Drugs - June 10, 2019 Category: Drugs & Pharmacology Source Type: research

The influence of the coadministration of the p-glycoprotein modulator elacridar on the pharmacokinetics of lapatinib and its distribution in the brain and cerebrospinal fluid
Conclusion This study showed that elacridar influenced the pharmacokinetics of lapatinib. The inhibition of ABCB1 and ABCG2 transporters by elacridar substantially enhanced the penetration of lapatinib into the CSF and BT. The blocking of protein transporters could become indispensable in the treatment of patients with breast cancer and brain metastases. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 8, 2019 Category: Drugs & Pharmacology Source Type: research

CKT0353, a novel microtubule targeting agent, overcomes paclitaxel induced resistance in cancer cells
SummaryMicrotubule targeting agents (MTAs) are extensively used in cancer treatment and many have achieved substantial clinical success. In recent years, targeting microtubules to inhibit cell division has become a widespread pharmaceutical approach for treatment of various cancer types. Nevertheless, the development of multidrug resistance (MDR) in cancer remains a major obstacle for successful application of these agents. Herein, we provided the evidence that CKT0353, α-branched α,β-unsaturated ketone, possesses the capacity to successfully evade the MDR phenotype as an MTA. CKT0353 induced G2/M phase ar...
Source: Investigational New Drugs - June 8, 2019 Category: Drugs & Pharmacology Source Type: research

Novel thiosemicarbazones induce high toxicity in estrogen-receptor-positive breast cancer cells (MCF7) and exacerbate cisplatin effectiveness in triple-negative breast (MDA-MB231) and lung adenocarcinoma (A549) cells
SummaryCis-diamminedichloroplatinum(II) (CDDP), known as cisplatin, has been extensively used against breast cancer, which is the most frequent cancer among women, and lung cancer, the leading cancer that causes death worldwide. Novel compounds such as thiazole derivatives have exhibited antiproliferative activity, suggesting they could be useful against cancer treatment. Herein, we synthesized two novel thiosemicarbazones and an aldehyde to combine with CDDP to enhance efficacy against ER-positive breast MCF7 cancer cells, triple-negative/basal-B mammary carcinoma cells (MDA-MB231) and lung adenocarcinoma (A549) human cel...
Source: Investigational New Drugs - June 8, 2019 Category: Drugs & Pharmacology Source Type: research

Activation of IGF-1R pathway and NPM-ALK G1269A mutation confer resistance to crizotinib treatment in NPM-ALK positive lymphoma
SummaryALK-positive anaplastic large cell lymphoma (ALCL) represents a subset of non-Hodgkin ’s lymphoma that is treated with crizotinib, a dual ALK/MET inhibitor. Despite the remarkable initial response, ALCLs eventually develop resistance to crizotinib. ALK inhibitor resistance in tumors is a complex and heterogeneous process with multiple underlying mechanisms, including ALK gene ampli fication, ALK kinase domain mutation, and the activation of various bypass signaling pathways. To overcome resistance, multiple promising next-generation ALK kinase inhibitors and rational combinatorial strategies are being develope...
Source: Investigational New Drugs - June 8, 2019 Category: Drugs & Pharmacology Source Type: research

A phase II study of the orally administered negative enantiomer of gossypol (AT-101), a BH3 mimetic, in patients with advanced adrenal cortical carcinoma
Conclusions AT-101 had no meaningful clinical activity in this study in patients with advanced ACC, but demonstrated feasibility of prospective therapeutic clinical trials in this rare cancer. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 6, 2019 Category: Drugs & Pharmacology Source Type: research

Sequential therapy with sorafenib and regorafenib for advanced hepatocellular carcinoma: a multicenter retrospective study in Japan
This study aimed to assess the safety and efficacy of sequential therapy with sorafenib and regorafenib in patients with advanced HCC by analysis of outcomes in clinical practice with the aim to complement phase III findings.Methods The medical records of patients with advanced HCC receiving regorafenib were retrieved to collect data on sorafenib administration at seven Japanese institutions. Radiological responses and adverse events were evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1 and the Common Terminology Criteria for Adverse Events version 4.0, respectively.Results Before March 2018, 44...
Source: Investigational New Drugs - June 6, 2019 Category: Drugs & Pharmacology Source Type: research

Effects of chemotherapy on placental development and function using in vitro culture of human primary cytotrophoblasts
Discussion The most commonly used chemotherapeutic drugs are well supported in vitro by syncytiotrophoblasts, except for epirubicin, which was very cytotoxic. Chemotherapy perturbed the expression of genes normally upregulated during placental differentiation and angiogenesis but not the expression of the drug transporters. Further studies looking at the effect of combination therapy and the transporter capacities to reject the drugs will be needed to better define the effects of chemotherapy on placental development and function. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 3, 2019 Category: Drugs & Pharmacology Source Type: research

Pharmacological effects of the simultaneous and sequential combinations of trifluridine/tipiracil (TAS-102) and 5-fluorouracil in fluoropyrimidine-sensitive colon cancer cells
SummaryThe aim of this study was to investigate possible synergistic effects in vitro of trifluridine/tipiracil (TAS-102) and 5-fluoruracil (5-FU) on fluoropyrimidine-sensitive colon cancer cell lines of different mutational status in order to build a rational basis for the future use of this combination therapy in adjuvant settings or as a first-line treatment for metastatic disease. Proliferation assays were performed on HT-29 (B-raf mutated), SW-620 (ras mutated), and Caco-2 (wild type) colon cancer cell lines exposed to 120-h treatments of 5-FU, TAS-102 and their different combination schedules (simultaneous, sequentia...
Source: Investigational New Drugs - June 1, 2019 Category: Drugs & Pharmacology Source Type: research

Phase II study of avelumab in multiple relapsed/refractory germ cell cancer
This study aimed to determine the efficacy and safety of avelumab, a PD-L1 inhibitor, in patients with GCTs.Methods In this phase 2 study, patients with multiple relapsed and/or refractory GCTs were treated with avelumab at a dose of 10  mg/kg administered biweekly until progression or unacceptable toxicity. The primary endpoint was 12-week progression-free survival (PFS). Fifteen evaluable patients had to be enrolled in the first cohort, and if
Source: Investigational New Drugs - June 1, 2019 Category: Drugs & Pharmacology Source Type: research

Increasing complexity in oncology phase I clinical trials
SummaryClinical trials in oncology have become increasingly complex because of incorporation of predictive biomarkers and patient selection based on molecular profiling of tumors. We have examined the change in procedures and work intensity in phase 1 oncology trials over the years with several parameters used as surrogates of complexity. Categories that were included as events were clinical evaluations, pharmacokinetic (PK) laboratory tests, non-PK laboratory tests, specific molecular or histological characteristics, questionnaires and subjective assessments, routine clinical and physical examinations, imaging, invasive p...
Source: Investigational New Drugs - May 28, 2019 Category: Drugs & Pharmacology Source Type: research

Induction of endoplasmic reticulum stress by aminosteroid derivative RM-581 leads to tumor regression in PANC-1 xenograft model
SummaryThe high fatality and morbidity of pancreatic cancer have remained almost unchanged over the last decades and new clinical therapeutic tools are urgently needed. We determined the cytotoxic activity of aminosteroid derivatives RM-133 (androstane) and RM-581 (estrane) in three human pancreatic cancer cell lines (BxPC3, Hs766T and PANC-1). In PANC-1, a similar level of antiproliferative activity was observed for RM-581 and RM-133 (IC50 = 3.9 and 4.3 μM, respectively), but RM-581 provided a higher selectivity index (SI = 12.8) for cancer cells over normal pancreatic cells than RM-133...
Source: Investigational New Drugs - May 28, 2019 Category: Drugs & Pharmacology Source Type: research

Combination treatment of cancer cells with pan-Akt and pan-mTOR inhibitors: effects on cell cycle distribution, p-Akt expression level and radiolabelled-choline incorporation
Conclusions Pan-mTOR and pan-Akt inhibition may be highly effective in cancer treatment and measuring changes in choline uptake could be useful in detecting efficacious drug combinations. (Source: Investigational New Drugs)
Source: Investigational New Drugs - May 28, 2019 Category: Drugs & Pharmacology Source Type: research

Clinical outcomes of patients with G1/G2 neuroendocrine tumors arising from foregut or hindgut treated with somatostatin analogs: a retrospective study
SummaryNeuroendocrine tumors (NET) are rare tumors for which somatostatin analogs (SSA) are used not only for symptom control due to a functioning tumor, but also for the disease control of unresectable NET. The efficacy of SSA for midgut NET has been verified by previous studies, but insufficient evidence exists for SSA treatment of NET in the foregut and hindgut (F/H-NET). The aim of this retrospective study was to evaluate the efficacy of SSA for unresectable F/H-NET. Patients with unresectable F/H-NET treated with SSA between February 2011 and August 2017 at our hospital were retrospectively reviewed. Parameters of eff...
Source: Investigational New Drugs - May 28, 2019 Category: Drugs & Pharmacology Source Type: research

HER-targeted tyrosine kinase inhibitors enhance response to trastuzumab and pertuzumab in HER2-positive breast cancer
This study evaluated the anti-proliferative effects of adding anti-HER2 tyrosine kinase inhibitors (TKIs) to trastuzumab and pertuzumab in HER2-positive breast cancer cells. Afatinib was tested alone and in combination with trastuzumab in HER2-positive breast cancer cell lines. TKIs (lapatinib, neratinib, afatinib) combined with trastuzumab and/or pertuzumab were tested in 3 cell lines, with/without amphiregulin and heregulin-1 β. Seven of 11 HER2-positive cell lines tested were sensitive to afatinib (IC50 
Source: Investigational New Drugs - May 28, 2019 Category: Drugs & Pharmacology Source Type: research

Phase I study of the indoleamine 2,3-dioxygenase 1 inhibitor navoximod (GDC-0919) as monotherapy and in combination with the PD-L1 inhibitor atezolizumab in Japanese patients with advanced solid tumours
This study investigated the safety, tolerability and pharmacokinetics of navoximod alone and in combination with atezolizumab in Japanese patients with advanced solid tumours. This was a phase I, open-label, dose-escalation study. Patients received monotherapy with navoximod 400  mg, 600 mg or 1000 mg orally twice daily (BID) in Stage 1 and navoximod 200 mg, 400 mg, 600 mg or 1000 mg orally BID plus atezolizumab 1200 mg intravenously every 21 days in Stage 2. Objectives included safety, tolerability, efficacy and pharmacokinetic outcomes.Overall, 20 patients were e nrolled (Stag...
Source: Investigational New Drugs - May 24, 2019 Category: Drugs & Pharmacology Source Type: research

Entrectinib resistance mechanisms in ROS1 -rearranged non-small cell lung cancer
SummaryEntrectinib is a pan-tyrosine-kinase inhibitor that targets oncogenic rearrangements inNTRK,ROS1 andALK. The combined results of two clinical trials demonstrated the efficacy of entrectinib inROS1-rearranged NSCLC. Because the development of drug resistance is inevitable, it would be helpful to determine the mechanisms of entrectinib resistance in aROS1-rearranged tumor model so that future therapeutic strategies can be developed. Here, we characterized the molecular basis of resistance in entrectinib-resistantROS1-rearranged HCC78 cells (HCC78ER cells). These cells were analyzed by next-generation sequencing and ge...
Source: Investigational New Drugs - May 24, 2019 Category: Drugs & Pharmacology Source Type: research

Reduced expression of annexin A1 promotes gemcitabine and 5-fluorouracil drug resistance of human pancreatic cancer
SummaryIntrinsic chemoresistance is the main reason for the failure of human pancreatic ductal adenocarcinoma (PDAC) therapy. To identify the candidate protein, we compared the protein expression profiling of PDAC cells and its distinct surviving cells following primary treatment with gemcitabine (GEM) and 5-fluorouracil (5-FU) by two-dimensional electrophoresis combined with liquid chromatography –mass spectrometry or mass spectrometry. A total of 20 differentially expressed proteins were identified, and annexin A1 (ANXA1) was analyzed for further validation. The functional validation showed that the downregulation ...
Source: Investigational New Drugs - May 23, 2019 Category: Drugs & Pharmacology Source Type: research

Assessment of the cytotoxic effects of aporphine prototypes on head and neck cancer cells
Conclusion Our results revealed that APO, C1, and A5 exhibit cytotoxic effects in HNSCC cells. The mechanisms of action appear to be partly via the generation of DNA damages and apoptosis induction through Caspase-3 pathway activation. This study provides preclinical data that suggest a potential therapeutic role for APO, C1, and A5 against head and neck cancer cells. (Source: Investigational New Drugs)
Source: Investigational New Drugs - May 17, 2019 Category: Drugs & Pharmacology Source Type: research

Cardamonin, a natural chalcone, reduces 5-fluorouracil resistance of gastric cancer cells through targeting Wnt/ β-catenin signal pathway
Conclusions Overall, this study revealed that cotreatment of cardamonin and 5-FU could strongly potentiate the antitumor activity of 5-FU, and put forth cardamonin as a rational therapeutic strategy for drug-resistant GC treatment. (Source: Investigational New Drugs)
Source: Investigational New Drugs - May 17, 2019 Category: Drugs & Pharmacology Source Type: research