Good Antitumor Efficacy Research Articles

Dynamics-Based Discovery of Novel, Potent Benzoic Acid Derivatives as Orally Bioavailable Selective Estrogen Receptor Degraders for ERα+ Breast Cancer.

The estrogen receptor α (ERα) is identified as an effective target for the treatment of ERα+ breast cancer; thus, discovery of novel selective estrogen receptor degraders (SERDs) are developed as an effective method to overcome the resistance of breast cancer. Herein, the hot-spot residues for protein-ligand interaction between SERDs and ERα are analyzed by molecular dynamic simulation technology, focusing on the hot-spot residues for four series of designed and synthesized SERDs. SAR studies revealed that while the acrylic acid moiety of AZD9496 is scaffold hopping into benzoic acid, compound D24 exhibits potent binding affinity with ERα, good degradation efficacy of ERα, and inhibitory effect against the MCF-7 breast cancer cell line. Besides, D24 also displays good antitumor efficacy in the MCF-7 human breast cancer xenograft model in vivo, favorable pharmacokinetic properties, excellent druggability, and good safety property, making D24 as a promising drug candidate of SERD for further evaluation.

Biodistribution and efficacy of the anticancer drug, oxaliplatin palmitate acetate, in mice

Oxaliplatin palmitate acetate (OPA), a platinum (IV) oxaliplatin derivative, was previously designed with the aim to improve the platinum-based anti-cancer therapy. In this work, we further explore the potential of OPA in extensive in vitro and in vivo studies. OPA in pancreatic (BxPC3-luc), lung (NCI-H1993) and liver (Hep3B) cancer cell lines showed a higher toxicity in comparison to oxaliplatin. The in vitro release kinetic experiments of OPA from the nanoparticles (NPs) under sink conditions exhibited a very rapid profile. Furthermore, OPA cannot be considered a prodrug of oxaliplatin, based on the OPA intact molecule pharmacokinetic profile study in rats. The formation of oxaliplatin from the biodegradation of OPA ranges only from 5% to 7% and both drugs were rapidly eliminated from the plasma. Pharmacokinetics of OPA PLGA nanoparticles in mice showed that nanoparticles failed to prolong the release of OPA in the plasma and did not add any therapeutic benefit over OPA solution, as suggested by the rapid in vitro release of OPA from nanoparticles. In pancreatic xenograft BxPC3-luc cancer model, both OPA in solution and OPA nanoparticles inhibited the tumor growth, equally and significantly, as compared to oxaliplatin. In liver xenograft Hep3B cancer model, OPA solution and cisplatin demonstrated good and similar antitumor efficacy. In lung xenograft NCI-H1993 cancer model, OPA solution, with a significant antitumor efficacy, was superior to cisplatin, which did not differ from the vehicle. In conclusion, OPA may offer a promising advance in platinum-based chemotherapy against various forms of cancers in an adequate dose and schedule.

Delivery of Rapamycin by Liposomes Synergistically Enhances the Chemotherapy Effect of 5-Fluorouracil on Colorectal Cancer.

BackgroundRapamycin is a promising agent for treating tumors, but clinical applications of rapamycin are limited due to its poor water solubility and low bioavailability. This paper constructs a liposome delivery system for rapamycin to improve the effect in treating colorectal cancer.MethodsWe prepared the rapamycin liposomes using the ethanol injection method. The cellular uptake and biodistribution were detected by LC-MS and in vivo imaging system. MTT assay, transwell migration experiment, flow cytometry, and Western blot analysis evaluated the antitumor effect of rapamycin liposomes in vitro. Furthermore, HCT-116 tumor-bearing mice were used to assess the therapeutic efficacy of rapamycin liposomes in vivo.ResultsThe prepared rapamycin liposomes had a particle size of 100±5.5 nm and with a narrow size distribution. In vitro cellular uptake experiments showed that the uptake of rapamycin liposomes by colorectal cells was higher than that of free rapamycin. Subsequently, in vivo imaging experiments also demonstrated that rapamycin liposomes exhibited higher tumor accumulation. Therefore, the ability of rapamycin liposomes to inhibit tumor proliferation, migration and to induce tumor apoptosis is superior to that of free rapamycin. We also demonstrated in vivo good antitumor efficacy of the rapamycin liposomes in HCT-116 xenograft mice. In addition, rapamycin liposomes and 5-FU can synergistically improve the efficacy of colorectal cancer via the Akt/mTOR and P53 pathways.ConclusionCollectively, rapamycin liposomes are a potential treatment for colorectal cancer, as it not only improves rapamycin’s antitumor effect but also synergistically enhances 5-FU’s chemotherapy effect.

A Phase I/II Study (JACKPOT8) of DZD4205, a Selective JAK1 Inhibitor, in Refractory or Relapsed Peripheral T- Cell Lymphoma

Background: Peripheral T-Cell Lymphoma (PTCL) is an aggressive malignancy which lacks effective treatment. Emerging data suggests that the JAK-STAT pathway may play an important role in mediating pathogenesis of PTCL. DZD4205 (AZD4205) is an orally available, potent and highly selective JAK1 inhibitor. In T-cell lymphoma cell lines, DZD4205 modulates pSTAT3 pathway and suppresses cell proliferation, and in tumor xenograft models, DZD4205 exhibits dose-dependent anti-tumor activities, with good correlation with drug exposure and modulations of pSTAT3 in tumor tissues. A phase I/II study (JACKPOT8) was initiated to assess the safety, tolerability, pharmacokinetics and anti-tumor efficacy of DZD4205 in patients with refractory/relapsed (r/r) PTCL. Methods: The JACKPOT8 study (ClinicalTrials.gov Identifier: NCT04105010) included two parts: Part A, dose escalation and Part B, dose expansion. In Part A, patients with r/r PTCL who have progressed on or were refractory to systemic therapy will be enrolled and treated with DZD4205 at two different dose levels, 150 mg or 250 mg once daily. In Part B, patients will receive DZD4205 treatment at a defined dose. The primary objective is to assess the safety and tolerability of DZD4205, and the secondary objectives include anti-tumor efficacy and pharmacokinetics. Evaluation of safety/tolerability and tumor response will be based on the CTCAE version 5.0 and 2014 Lugano classification, respectively. Patients will be treated until disease progression, intolerance to adverse events, or withdrawal of consent. Results: As of June 30, 2020, a total of 23 patients with r/r PTCL were enrolled and received DZD4205 at 150 mg (n = 19) or 250 mg (n = 4) once daily. Patient characteristics: median age (range): 65.0 years (34-79); median prior systemic therapies (range): 2 lines (1-8). Four patients had undergone prior hematopoietic stem cell transplantation (HSCT). Six patients had bone marrow involvement at the study entry. Histological subtypes included peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) (n = 10, 43.5%), angioimmunoblastic T-cell lymphoma (AITL) (n = 10, 43.5%), ALK-negative anaplastic large cell lymphoma (ALCL ALK-) (n = 2, 8.7%) and extra-nodal nasal NK/T-cell lymphoma (NKTCL) (n = 1, 4.3%) . Preliminary data showed that 20 patients experienced treatment emergent adverse events (TEAEs), among whom 13 (56.5%) had ≥ grade 3 TEAEs. Based on local investigators' assessment, eight patients (34.8%) had ≥ grade 3 TEAEs which were considered to be related to DZD4205. The most common (> 5% incidence) DZD4205-related TEAEs (any grade) included thrombocytopenia (n = 6, 26.1%), neutropenia (n = 4, 17.3%), decreased appetite (n = 3, 13.0%), nausea (n = 2, 8.7%), interstitial lung disease (n = 2, 8.7%) and pneumonia (n = 2, 8.7%). Most TEAEs were manageable with dose interruption and reduction. Preliminary PK data is available in 20 patients (n = 19 at 150 mg, n = 1 at 250 mg). Exposure at 250 mg is higher than 150 mg following a single and multiple dose. As expected from long t1/2 of DZD4205, accumulation of about 3 folds in AUC was observed. DZD4205 had flat PK profile with small difference between Css,max and Css,min after 22 days of once daily dosing, which is an optimal PK profile to maintain DZD4205 concentrations above effective levels throughout the dosing interval. As of June 30, 2020, 22 patients (n = 19 at 150 mg, n = 3 at 250 mg) had at least one post-treatment Lugano assessment. In 150 mg cohort, 8 out of 19 patients showed tumor response, with objective response rate (ORR) of 42%, among whom 4 (21%) had complete response (CR) and another 4 (21%) partial response (PR). In 250 mg cohort, 1 out of 3 patients showed tumor response, with ORR of 33%. Tumor response was observed in subtypes including AITL, PTCL-NOS, ALCL (ALK-) and NKTCL. At the data cut-off date, the longest duration on treatment was > 8 months. Patient enrolment is ongoing. Updated clinical data will be shared at the meeting. Conclusion: DZD4205 shows good tolerability, pharmacokinetic profiles and promising anti-tumor efficacy in patients with r/r PTCL, indicating its potential as a therapeutic option for this unmet medical need. Disclosures Kim: Donga: Research Funding; Kyowa-Kirin: Research Funding; Roche: Research Funding; Johnson&Johnson: Research Funding; Celltrion: Research Funding; Mundipharma: Research Funding. Yoon:Celltrion: Honoraria; Samyang: Research Funding; Amgen, Chongkundang, Celgene, Astrazeneca: Consultancy. Wang:Dizal Pharmaceuticals: Current Employment. Li:Dizal Pharmaceuticals: Current Employment. Huang:Dizal Pharmaceuticals: Current Employment. Deng:Dizal Pharmaceuticals: Current Employment. Chen:Dizal Pharmaceuticals: Current Employment. Yang:Dizal Pharmaceuticals: Current Employment.

Huaier Granule Combined with Tegafur Gimeracil Oteracil Potassium Promotes Stage IIb Gastric Cancer Prognosis and Induces Gastric Cancer Cell Apoptosis by Regulating Livin.

Gastric cancer is one of the most common malignancies worldwide, with high morbidity and poor survival rate. Its prognosis remains unsatisfactory, with a 5-year survival rate of <30%. Studies have indicated that Huaier granules have good antitumor efficacy and safety in several solid malignant tumors. Recent studies have also found that Huaier polysaccharides can promote apoptosis in numerous tumor cells, although only few studies have focused on the effects of Huaier granules on gastric cancers and the mechanisms underlying their antitumor role. We retrospectively evaluated stage IIb gastric cancer patients at Xiangya Hospital, Central South University, through our outpatient system from January 2013 to December 2015. Fifty-four patients were in the Huaier+Tegafur Gimeracil Oteracil Potassium (TGOP) group and 72 in the TGOP group. Further, we conducted CCK8, colony formation, Annexin V-FITC/PI, Western blot, RT-PCR, and plasmid transfection assays to analyze the mechanism by which Huaier polysaccharides play an antitumor role. We confirmed that Huaier granules combined with Tegafur Gimeracil Oteracil Potassium could promote patient prognosis, with a better disease-free survival rate (51.32 ± 2.23 vs. 44.19 ± 2.26, p = 0.034) and overall survival rate (56.81 ± 1.32 vs. 51.32 ± 1.69, p = 0.020). Moreover, through cell proliferation assays, Western blot, RT-PCR, and detection of Livin expression at the mRNA and protein levels, we found that Huaier polysaccharides could promote gastric cancer cell apoptosis and inhibit gastric cancer cell proliferation in a time- and dose-dependent manner. Finally, we demonstrated that Huaier polysaccharides promote gastric cancer cell apoptosis through the regulation of Livin expression. Overexpression of Livin reversed the gastric cell apoptosis induced by Huaier polysaccharides. Huaier granules combined with Tegafur Gimeracil Oteracil Potassium ameliorated stage IIb gastric cancer prognosis and induced gastric cancer cell apoptosis by regulating Livin.

A Nano Drug Delivery System Based on Angelica sinensis Polysaccharide for Combination of Chemotherapy and Immunotherapy.

Combination of chemotherapy and immunotherapy has been a promising strategy in cancer treatment. Polysaccharides from Angelica sinensis (AP), a well-known Chinese herbal medicine, have been proved to have good immunomodulatory activity. In the present study, an enzyme-sensitive tumor-targeting nano drug delivery system (AP-PP-DOX (doxorubicin), PP stood for peptide) was constructed. In this system, Angelica polysaccharides act as not only carriers to targeted delivery of drugs to tumor tissue but also effectors to improve tumor microenvironment and enhance immune function, resulting in synergistic antitumor effect with chemotherapy drugs. The structure of this conjugate was confirmed by FI-IR and 1H-NMR. The particle size and zeta potential of the nanoparticles were 129.00 ± 3.32 nm and −28.45 ± 0.22 mV, respectively. Doxorubicin (DOX) and AP could be quickly released from the AP-PP-DOX under the presence of matrix metalloproteinase 2 (MMP2). The released DOX showed good antitumor efficacy in vitro. The treatment of released AP moiety increased the expression of IL-2, while that of IL-10 was decreased, showing potential in restoring Th1/Th2 immune balance in tumor microenvironment. In a word, this drug delivery system, with specific tissue targeting and tumor microenvironment improvement, will open a new avenue for combination treatment of cancer.

Multifunctional STING‐Activating Mn3O4@Au‐dsDNA/DOX Nanoparticle for Antitumor Immunotherapy

The promise of immunotherapy for cancer therapy has not been fully fulfilled because portions of tumors are immunosuppressive. To tackle this challenge, the initiation of immune system by stimulator of interferon genes (STING) pathway is explored and multifunctional STING-activating nanoparticles are rationally designed for synergistic antitumor therapy. The STING-activating nanoparticles have a formulation of Mn3 O4 @Au-dsDNA/DOX, where dsDNA is used to activate STING for immunotherapy and doxorubicin (DOX) is chosen as a model drug for chemotherapy. The STING-mediated immunity is activated, inducing interferon-β (IFN-β) production, increasing T cell priming, and enhancing effector T cell infiltration. Combined with chemotherapy, STING-mediated immunotherapy shows good antitumor efficacy by inhibiting tumor growth and prolonging survival rate in vivo. The promise of cancer immunotherapy can be fulfilled by combining novel antitumor immunity with innovative nanotechnology, and chemotherapy and targeted therapies.

PCC0208023, a potent SHP2 allosteric inhibitor, imparts an antitumor effect against KRAS mutant colorectal cancer

The non-receptor tyrosine phosphatase SHP2, encoded by PTPN11, plays an indispensable role in tumors driven by oncogenic KRAS mutations, which frequently occur in colorectal cancer. Here, PCC0208023, a potent SHP2 allosteric inhibitor, was synthesized to evaluate its inhibitory effects against the SHP2 enzyme, and the KRAS mutant colorectal cancer in vitro and in vivo, and its impart on the RAS/MAPK pathway. Consistent with an allosteric mode of inhibition, PCC0208023 can non-competitively inhibit the activity of full-length SHP2 enzyme, but lacks activity against the free catalytic domain of SHP2. Furthermore, PCC0208023 inhibited the proliferation of KRAS mutation-driven human colorectal cancer cells by inhibiting the RAS/MAPK signaling pathway in vitro. Importantly, PCC0208023 displayed good anti-tumor efficacy against KRAS-driven LS180 and HCT116 xenograft models in nude mice with the decreased Ki67 and p-ERK level, and increased cleaved caspase-3 expression in tumors. Interestingly, PCC0208023 maintained high levels in LS180 tumors within 24 h after administration and was mainly distributed in both intestines and lungs. Molecular docking studies revealed a higher affinity of PCC0208023 with key residues in the SHP2 allosteric pocket than RMC-4550. PCC0208023 deserves further optimization to identify additional low-toxic and potent SHP2 allosteric inhibitors with novel scaffolds for the treatment of patients with KRAS mutation-positive colorectal cancer.

Interface crosslinked mPEG-b-PAGE-b-PCL triblock copolymer micelles with high stability for anticancer drug delivery

The stability of polymeric micelles is a key property for anticancer drug delivery. In this study, a novel amphiphilic triblock copolymer, methoxy poly(ethylene glycol)-b-poly(allyl glycidyl ether)-b-poly(ε-caprolactone) (mPEG-b-PAGE-b-PCL), with different hydrophobic lengths was designed and synthesized using the combination of two successive ring-opening polymerizations. The products were characterized using 1H NMR and gel permeation chromatography (GPC). The triblock copolymers could self-assemble into micelles to encapsulate doxorubicin (DOX). The diameter of the DOX-loaded micelles increased from 63 to 92 nm with increasing PCL block length in the copolymer composition. The interface of the mPEG-b-PAGE-b-PCL micelles was crosslinked by a thiol-ene reaction with 1,4-butanedithiol. The stability, drug release and in vitro cytotoxicity of the DOX-loaded micelles were studied. The results showed that the DOX-loaded micelles could be effectively endocytosed by cancer cells and have good antitumor efficacy. In addition, the crosslinked micelles (CLMs) had better tumor accumulation than the noncrosslinked micelles (NCLMs) after intravenous injection using the lipophilic dye DiR.

Soybean lecithin stabilizes disulfiram nanosuspensions with a high drug-loading content: remarkably improved antitumor efficacy

Disulfiram (DSF) has been considered as “Repurposing drug” in cancer therapy in recent years based on its good antitumor efficacy. DSF is traditionally used as an oral drug in the treatment of alcoholism. To overcome its rapid degradation and instability, DSF nanosuspensions (DSF/SPC-NSps) were prepared using soybean lecithin (SPC) as a stabilizer of high drug-loaded content (44.36 ± 1.09%). Comprehensive characterization of the nanosuspensions was performed, and cell cytotoxicity, in vivo antitumor efficacy and biodistribution were studied. DSF/SPC-NSps, having a spherical appearance with particle size of 155 nm, could remain very stable in different physiological media, and sustained release. The in vitro MTT assay indicated that the cytotoxicity of DSF/SPC-NSps was enhanced remarkably compared to free DSF against the 4T1 cell line. The IC50 value decreased by 11-fold (1.23 vs. 13.93 μg/mL, p < 0.01). DSF/SPC-NSps groups administered via intravenous injections exhibited better antitumor efficacy compared to the commercial paclitaxel injection (PTX injection) and had a dose-dependent effect in vivo. Notably, DSF/SPC-NSps exhibited similar antitumor activity following oral administration as PTX administration via injection into a vein. These results suggest that the prepared nanosuspensions can be used as a stable delivery vehicle for disulfiram, which has potential application in breast cancer chemotherapy.

Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastoma

Simultaneous inhibition of MDM2 and CDK4 may be an effective treatment against glioblastoma. A collection of chiral spirocyclic tetrahydronaphthalene (THN)-oxindole hybrids for this purpose have been developed. Appropriate stereochemistry in THN-fused spirooxindole compounds is key to their inhibitory activity: selectivity differed by over 40-fold between the least and most potent stereoisomers in time-resolved FRET and KINOMEscan® in vitro assays. Studies in glioblastoma cell lines showed that the most active compound ent-4g induced apoptosis and cell cycle arrest by interfering with MDM2 -P53 interaction and CDK4 activation. Cells treated with ent-4g showed up-regulation of proteins involved in P53 and cell cycle pathways. The compound showed good anti-tumor efficacy against glioblastoma xenografts in mice. These results suggested that rational design, asymmetric synthesis and biological evaluation of novel tetrahydronaphthalene fused spirooxindoles could generate promising MDM2-CDK4 dual inhibitors in glioblastoma therapy.

Abstract 1326: WSD0922: A BBB penetrable EGFR/EGFRVIII inhibitor for the treatment of GBM and metastatic CNS tumor

Abstract Aberrant activity caused by EGFRm+ (EGFRvIII/Del19/L858R) is implicated in the brain tumors such as GBM and DIPG, and metastatic CNS tumors of NSCLC, and cancer of HNSCC. To date, approved EGFRi has limited efficacy against brain tumors due to insufficient BBB penetration and/or poor activity against EGFRvIII. Moreover, GBM is a whole-brain disease and needs a BBB penetrable therapy for killing tumor cells beyond intact BBB. We report that WSD0922, a novel selective EGFRi, displays potent activity, excellent CNS penetration, good safety profile and preclinical anti-tumor efficacy. The IC50 of WSD0922 against EGFRm+ &amp;lt;10nM and the ex-vivo GI50 in GBM PDX with EGFRvIII is ~20nM. WSD0922 is highly selective over other kinases. WSD0922 treatment resulted in dose dependent inhibition on EGFRvIII phosphorylation and AKT phosphorylation in GBM PDX model and the in vivo PD modulation correlated well with PK and efficacy. WSD0922 treatment significantly prolonged the survival of mice with intracranial tumor of EGFRm+ NSCLC. WSD0922 treatment resulted in tumor regression on cetuximab resistant PDX model of HNSCC. In screening platform of squamous lung cancer PDX models, WSD0922 demonstrated remarkable tumor regression in 3 PDX models (platinum sensitive/insensitive/EGFRm+). WSD0922 is well tolerated in GLP tox at dose ~10x clinical equivalent dose. In addition, WSD0922 is predicted to be CNS penetrable with decent PK in human. The phase 1 clinical trial in US will be initiated in early 2019 with a design of 3+3 basket trial. Taken together, our data provide a good rationale for WSD0922 to be developed toward clinic for the treatment of patients with GBM, HNSCC (EGFR and/or EGFRvIII) and CNS metastasis of NSCLC (EGFRm+). Citation Format: Wei Zhong, Jinqiang Zhang, Ahihua Mu, Claire Sun. WSD0922: A BBB penetrable EGFR/EGFRVIII inhibitor for the treatment of GBM and metastatic CNS tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1326.

The immunostimulatory effects and pro-apoptotic activity of rhCNB against Lewis lung cancer is mediated by Toll-like receptor 4.

BackgroundRecombinant human calcineurin B subunit (rhCNB) has been shown to be an immune‐stimulatory protein promoting cytokine production and inducing phenotypic maturation of Dendritic cells (DCs). In vivo, it has good antitumor efficacy, and has potential as an antitumor drug. Exogenous rhCNB was found to be internalized into tumor cells via the Toll‐like receptor 4 (TLR4) complex, but it was not known whether its immuno‐modulatory and antitumor functions involved entry by this same route.MethodsThe production and secretion of the cytokines and chemokines in innate immune cells induced by rhCNB were determined by ELISA, and the expression of CD40, CD80, CD86, and MHCII was analyzed by FACs. Experimental Lewis lung cancer (LLC) model was prepared in C57 BL/6 wild‐type (WT) mice, TLR4−/− mice or their littermates by the inoculation of LLCs in their right armpit, and then administrated daily intraperitoneal injections (0.2 mL) of normal saline, rhCNB 20 mg/kg, and rhCNB 40 mg/kg, respectively.ResultsRecombinant human calcineurin B subunit promoted the production of antitumor cytokines by innate immune cells, and culture supernatants of rhCNB‐stimulated immune cells induced apoptosis of LLCs. In addition, rhCNB up‐regulated CD40, CD80, CD86, and MHCII expression in macrophages and DCs in TLR4+ cells but failed to do so in TLR4 deficient cells. rhCNB also induced the formation of CD4+ and CD8+T cells in splenocytes from WT mice, but not from TLR4‐deficient littermates. Intraperitoneal administration of WT C57BL/6 mice with rhCNB resulted in a 50% reduction in LLC tumor growth, but failed to inhibit tumor growth in TLR4−/− littermates.ConclusionsThe in vivo antitumor and immunomodulatory effects of rhCNB are mediated by the TLR4. This conclusion is important for the further understanding and development of rhCNB as an antitumor drug.

Design and Synthesis of Potent, Selective Inhibitors of Protein Arginine Methyltransferase 4 against Acute Myeloid Leukemia.

PRMT4 is a type I protein arginine methyltransferase and plays important roles in various cellular processes. Overexpression of PRMT4 has been found to be involved in several types of cancers. Selective and in vivo effective PRMT4 inhibitors are needed for demonstrating PRMT4 as a promising therapeutic target. On the basis of compound 6, a weak dual PRMT4/6 inhibitor, we constructed a tetrahydroisoquinoline scaffold through a cut-and-sew scaffold hopping strategy. The subsequent SAR optimization efforts employed structure-based approach led to the identification of a novel PRMT4 inhibitor 49. Compound 49 exhibited prominently high potency and selectivity, moderate pharmacokinetic profiles, and good antitumor efficacy in acute myeloid leukemia xenograft model via oral administration, thus demonstrating this compound as a useful pharmacological tool for further target validation and drug development in cancer therapy.

Combining structure- and property-based optimization to identify selective FLT3-ITD inhibitors with good antitumor efficacy in AML cell inoculated mouse xenograft model

FLT3 mutation is among the most common genetic mutations in acute myeloid leukemia (AML), which is also related with poor overall survival and refractory in AML patients. Recently, FLT3 inhibitors have been approved for AML therapy. Herein, a series of new compounds with pyrazole amine scaffold was discovered, which showed potent inhibitory activity against FLT3-ITD and significant selectivity against both FLT3-ITD and AML cells expressing FLT3-ITD. Compound 46, possessing the most promising cellular activity, blocked the autophosphorylation of FLT3 pathway in MV4-11 cell line. Furthermore, the apoptosis and downregulation of P-STAT5 were also observed in tumor cells extracted from the MV4-11 cell xenografts model upon compound 46 treatment. Compound 46 was also metabolically stable in vitro and suppressed tumor growth significantly in MV4-11 xenografts model in vivo. Compound 46 showed no toxicity to the viscera of mice and caused no decrease in body weight of mice. In conclusion, the results of this study could provide valuable insights into discovery of new FLT3 inhibitors, and compound 46 was worthy of further development as potential drug candidate to treat AML.

A Novel Multimodal NIR-II Nanoprobe for the Detection of Metastatic Lymph Nodes and Targeting Chemo-Photothermal Therapy in Oral Squamous Cell Carcinoma.

Current surgical treatment for oral squamous cell carcinoma (OSCC) must be as precise as possible to fully resect tumors and preserve functional tissues. Thus, it is urgent to develop efficient fluorescent probes to clearly identify tumor delineation, as well as metastatic lymph nodes. Chemo-photothermal therapy combination attracted a growing attention to increase anti-tumor effect in various types of cancer, including OSCC. In the present study, we designed a multimodal NIR-II probe that involves combining photothermal therapy with chemotherapy, imaging OSCC tumors and detecting metastatic lymph nodes.Methods: In this study, we synthesized a novel near infrared (NIR)-II probe named TQTPA [4,4'-((6,7-bis(4-(hexyloxy)phenyl)-[1,2,5]thiadiazolo [3,4-g]quinoxaline-4,9-diyl)bis(thiophene-5,2-diyl))bis(N,N-diphenylaniline)] via the Suzuki reaction and prepared multimodal nanoparticles (NPs) loading TQTPA and cis-dichlorodiammine platinum (CDDP) (HT@CDDP) by hyaluronic acid. The characteristics of the NPs, including their photothermal and imaging capabilities were investigated in vitro and in vivo. Their anti-tumor efficacy was evaluated using orthotopic, tongue tumor-bearing, nude mice.Results: The NPs possessed good stability and water solubility and were pH/hyaluronidase sensitive. The good tissue penetration quality and active targeting ability enabled the NPs to draw the outline of orthotopic tongue tumors and metastatic lymph nodes as small as 1 mm in nude mice by IR-808 under NIR exposure. In vitro and in vivo experiments validated the biocompatibility and low systematic toxicity of the NPs. At the same time, the NPs acted as multimodal therapy agents, combining photothermal therapy with chemotherapy.Conclusion: With a good imaging capability and anti-tumor efficacy, our NPs successfully outlined orthotopic tongue tumors and metastatic lymph nodes as well as enabled chemo-photothermal therapy combination. Our study established a solid foundation for the application of new clinical diagnosis and treatment patterns in the future.

Gambogic Acid-Loaded Polymeric Micelles for Improved Therapeutic Effect in Breast Cancer.

Gambogic acid (GA) possesses good anti-tumor efficacy in preclinical studies, however, its poor hydrophilicity, short blood circulation time and side effect limited its clinical application. In this work, monomethyl poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) copolymer was synthesized and used to encapsulate GA by a facile one-step solid dispersion and form nano-sized micelles (GA micelles). The GA micelles exhibited small average particle size (29±2 nm), high encapsulation efficiency (92.1±0.3%), and long drug release time-in vitro. Compared to free GA, GA micelles showed superior aqueous dispersity, better tumor cellular uptake, enhanced cytotoxicity and apoptosis induction effect against MCF-7 cells. Furthermore, in vivo studies demonstrated that GA micelles have better antitumor effect in the MCF-7 subcutaneous xenograft tumor model. Histopathological analysis of Ki-67 and TUNEL staining further proved that GA micelles could significantly suppress proliferation as well as increase the apoptosis of tumor cells. These results suggested that GA micelles could potentially improve therapeutic outcomes for breast cancer therapy.

Abstract 1672: Preclinical evaluation of WXFL1024H251, a potent second-generation HSP90 inhibitor

Abstract Objective: Heat Shock Protein 90 (Hsp90) is a molecular chaperone that mediates the post-translational stability of its protein substrates, many of which are onco-proteins. Hsp90 is emerging as an important target for cancer therapy because its inactivation may abrogate multiple signaling pathways simultaneously, irrespective of the mutational status of proteins involved. We disclose here our clinical candidate WXFL1024H251, a novel second-generation small-molecule Hsp90 inhibitor with a chemical structure unrelated to the first generation, the ansamycin family of Hsp90 inhibitors. Method: The anti-proliferative activity of WXFL1024H251 was evaluated in a variety of cancer cell lines in a 96-hour viability assay. QW, Q2W or TIW intravenous administration of at doses of 5~50 mg/kg was used to evaluate the in vivo anti-tumor activity of WXFL1024H251 in BT474 cell line-derived xenograft (CDX) breast cancer model. Effects of WXFL1024H251 on HSP90 function were assessed by western blot analysis of PD markers HSP70, Her2 and p-Her2 in the BT474 tumors. Result: A panel of 20 cancer cell lines were screened for sensitivity to WXFL1024H251. Proliferation of 2 cancer cell lines A549 and BT474 were potently inhibited by WXFL1024H251, with IC50 of 0.007 μM and 0.009 μM, respectively. A549 cell line has KRAS mutation and medium to high EGFR expression. BT474 is an ER+ and ERBB2+ breast cancer cell line. In the BT474 tumor model, 3 week treatment with WXFL1024H251 showed good antitumor efficacy with T/C values of 36% at 7.5 mg/kg Q2W and 45% at 10 mg/kg QW; toxicity were acceptable with both dosing regiments. Conclusion: These preclinical studies showed good antitumor efficacy of WXFL1024H251, which was associated with client protein maturation and HSP70 up-regulation in the tumor tissue. WXFL1024H251 may represent a novel promising clinical antitumor agent for treating breast cancer and other cancer types with high expression of HSP90. Citation Format: Xiaobing yan, Charles Z. Ding, Lihong Hu, Wei Huang, Shuhui Chen, Dongdong Wu, Jiahu Wu, Guoqiang Ma, Qiyao Zhang, Rui Gao, Yusong Zhu, Tiantian Dong, Yizhong Zhu, Caixia Yan, Yan Yan. Preclinical evaluation of WXFL1024H251, a potent second-generation HSP90 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1672.

Attenuated Bacteria as Immunotherapeutic Tools for Cancer Treatment.

The use of attenuated bacteria as cancer therapeutic tools has garnered increasing scientific interest over the past 10 years. This is largely due to the development of bacterial strains that maintain good anti-tumor efficacy, but with reduced potential to cause toxicities to the host. Because of its ability to replicate in viable as well as necrotic tissue, cancer therapy using attenuated strains of facultative anaerobic bacteria, such as Salmonella, has several advantages over standard treatment modalities, including chemotherapy and radiotherapy. Despite some findings suggesting that it may operate through a direct cytotoxic effect against cancer cells, there is accumulating evidence demonstrating that bacterial therapy acts by modulating cells of the immune system to counter the growth of the tumor. Herein, we review the experimental evidence underlying the success of bacterial immunotherapy against cancer and highlight the cellular and molecular alterations in the peripheral immune system and within the tumor microenvironment that have been reported following different forms of bacterial therapy. Our improved understanding of these mechanisms should greatly aid in the translational application of bacterial therapy to cancer patients.

Histopathological findings in colorectal liver metastases after electrochemotherapy.

Electrochemotherapy of colorectal liver metastases has been proven to be feasible, safe and effective in a phase I/II study. In that study, a specific group of patients underwent two-stage operation, and the detailed histopathological evaluation of the resected tumors is presented here. Regressive changes in electrochemotherapy-treated liver metastases were evaluated after the second operation (in 8–10 weeks) in 7 patients and 13 metastases when the treated metastases were resected. Macroscopic and microscopic changes were analyzed. Electrochemotherapy induced coagulation necrosis in the treated area encompassing both tumor and a narrow band of normal tissue. The area became necrotic, encapsulated in a fibrous envelope while preserving the functionality of most of the vessels larger than 5 mm in diameter and a large proportion of biliary structures, but the smaller blood vessels displayed various levels of damage. At the time of observation, 8–10 weeks after electrochemotherapy, regenerative changes were already seen in the peripheral parts of the treated area. This study demonstrates regressive changes in the whole electrochemotherapy-treated area of the liver. Further evidence of disruption of vessels less than 5 mm in diameter and preservation of the larger vessels by electrochemotherapy is provided. These findings are important because electrochemotherapy has been indicated for the therapy of metastases near major blood vessels in the liver to provide a safe approach with good antitumor efficacy.