The first-in-class anti-cancer agent ABTL0812 is effective in preclinical models of human endometrial cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e17070-e17070
Author(s):  
Eva Colàs Colàs ◽  
Nuria Eritja ◽  
Pau Muñoz-Guardiola ◽  
Sonia Sole-Sanchez ◽  
Cristian Moiola ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Endometrial Cancer ◽  
Mouse Model ◽  
Endometrial Adenocarcinoma ◽  
Preclinical Models ◽  
Phase Ib ◽  
Anti Cancer ◽  
Ishikawa Cells ◽  
Cancer Agent

e17070 Background: ABTL0812 is a first-in-class anti-cancer agent with a unique mechanism of action currently in Phase Ib/IIa clinical development for endometrial cancer and squamous NSCLC. ABTL0812 successfully culminated a Phase I clinical trial showing a high safety profile and long disease stabilizations, including 14-months stabilization in a patient with platinum-unresponsive Grade IIIC endometrial cancer with mutated PI3KCA and Akt. Methods: ABTL0812 synergy with paclitaxel and carboplatin was tested in vitro on Ishikawa cells by MTT assay. ABTL0812 in vivo anti-tumor activity was assessed in a PTEN-null inducible mouse model of endometrial adenocarcinoma development upon tamoxifen injection. In vivo synergy between ABTL0812 and paclitaxel was validated in a xenograft model orthotopically implanted with Ishikawa cells and between ABTL0812 and paclitaxel/carboplatin (P/C) in xenografts derived from a patient (PDX) with grade IIIC2 endometrial carcinoma with mutated PI3KCA. Results: ABTL0812 reduced paclitaxel and carboplatin IC50 by 1.5 and 2.1 times respectively in Ishikawa cells. Synergy with paclitaxel was found in Ishikawa orthoxenografts, showing a maximum Tumor Growth Inhibition (maxTGI) of 56,7±16,9% compared with 34.6±33.2% of paclitaxel group. ABTL0812 alone was effective reducing endometrial intraepithelial neoplasia formation in a mouse model of endometrial adenocarcinoma. Additionally, in an endometrial cancer PDX, ABTL0812 alone showed similar efficacy with reduced toxicity when compared with P/C and improved maxTGI when given in combination (ABTL0812: 45,2±17,5%; C/P*: 38,7±26,9%; ABTL0812+C/P*: 59.3±8.8%; *p=0.031). Conclusions: ABTL0812 has shown efficacy as a single agent and in combination with chemotherapy in preclinical models of endometrial cancer with mutations on PI3K/Akt pathway, which appears frequently over-activated in patients with these cancers. These results supported the application of ABTL0812 as a first line therapy in combination with chemotherapy for the Phase Ib/IIa clinical trial currently ongoing, positioning ABTL0812 as a potential therapeutic agent in the treatment of endometrial cancers bearing these genetic alterations.

scholarly journals Metformin induces Ferroptosis by inhibiting UFMylation of SLC7A11 in breast cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Jingjing Yang ◽  
Yulu Zhou ◽  
Shuduo Xie ◽  
Ji Wang ◽  
Zhaoqing Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Treatment ◽  
Morphological Changes ◽  
Tumor Model ◽  
Independent Manner ◽  
Regulated Cell Death ◽  
Anti Cancer ◽  
Cancer Agent ◽  
Approved Drugs

Abstract Background Ferroptosis is a newly defined form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxidation and is involved in various pathophysiological conditions, including cancer. Targeting ferroptosis is considered to be a novel anti-cancer strategy. The identification of FDA-approved drugs as ferroptosis inducers is proposed to be a new promising approach for cancer treatment. Despite a growing body of evidence indicating the potential efficacy of the anti-diabetic metformin as an anti-cancer agent, the exact mechanism underlying this efficacy has not yet been fully elucidated. Methods The UFMylation of SLC7A11 is detected by immunoprecipitation and the expression of UFM1 and SLC7A11 in tumor tissues was detected by immunohistochemical staining. The level of ferroptosis is determined by the level of free iron, total/lipid Ros and GSH in the cells and the morphological changes of mitochondria are observed by transmission electron microscope. The mechanism in vivo was verified by in situ implantation tumor model in nude mice. Results Metformin induces ferroptosis in an AMPK-independent manner to suppress tumor growth. Mechanistically, we demonstrate that metformin increases the intracellular Fe2+ and lipid ROS levels. Specifically, metformin reduces the protein stability of SLC7A11, which is a critical ferroptosis regulator, by inhibiting its UFMylation process. Furthermore, metformin combined with sulfasalazine, the system xc− inhibitor, can work in a synergistic manner to induce ferroptosis and inhibit the proliferation of breast cancer cells. Conclusions This study is the first to demonstrate that the ability of metformin to induce ferroptosis may be a novel mechanism underlying its anti-cancer effect. In addition, we identified SLC7A11 as a new UFMylation substrate and found that targeting the UFM1/SLC7A11 pathway could be a promising cancer treatment strategy.

A phase Ib study of NUC-3373 in combination with standard therapies in advanced/metastatic colorectal cancer (NuTide:302).

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 93-93
Author(s):  
Andrew L. Coveler ◽  
Farasat Kazmi ◽  
Kristen Keon Ciombor ◽  
Janet Graham ◽  
Lisa Jane Rodgers ◽  
...  
Keyword(s):  
Safety Profile ◽  
Safety Data ◽  
Resistance Mechanisms ◽  
Clinical Activity ◽  
Data Series ◽  
Rapid Progression ◽  
Phase Ib ◽  
Toxic Metabolites ◽  
Anti Cancer ◽  
Cancer Agent

93 Background: 5-FU is a key anti-cancer agent used across a broad range of tumors. The anti-cancer metabolite of 5-FU, fluorodeoxyuridine-monophosphate (FUDR-MP), binds and inhibits thymidylate synthase (TS), disrupting DNA synthesis and repair. 5-FU is often dosed with leucovorin (LV) to enhance the binding of FUDR-MP to TS. NUC-3373 is a targeted inhibitor of TS designed to bypass 5-FU resistance mechanisms associated with transport, activation and breakdown and avoid the generation of toxic metabolites such as FUTP and FBAL. NUC-3373 has a longer plasma t1/2 (~10 hours) than 5-FU (8-14 minutes), generating substantially higher intracellular levels of FUDR-MP and lower levels of the toxic metabolites FUTP and FBAL. Part 1 interim data from the NuTide:302 study demonstrated NUC-3373’s favorable PK and safety profile was unaffected by LV. Therefore, all subsequent patients in NuTide:302 are receiving NUC-3373 + LV. Here we present the next data series from NuTide:302. Methods: NuTide:302 is a 3-part, Phase Ib study in patients with advanced CRC who have relapsed after ≥2 prior lines of fluoropyrimidine- containing therapies. In Part 1, patients are receiving NUC-3373 with or without LV. In Part 2, NUC-3373 +LV is being administered in dose-escalation cohorts with either oxaliplatin (NUFOX) or irinotecan (NUFIRI). In Part 3, the NUFOX and NUFIRI regimens selected from Part 2 will be combined with biologics targeting VEGF and EGFR pathways. Results:36 patients have been treated in Part 1: 21 received 1500 mg/m2 NUC-3373 ± LV q2w; 11 received 1500 mg/m2NUC-3373 + LV q1w; and 4 received 2500 mg/m2 NUC-3373 + LV q1w. Clinical activity has been observed including tumor shrinkages and stabilization of disease for up to 5 months following rapid progression (≤2 months) on prior lines of therapy. One fluoropyrimidine-refractory patient demonstrated a 28% reduction in target lesions and achieved a stable disease of 5 months after rapid progression on CAPOX (2 months) and FOLFIRI (1.5 months). Safety data for all patients treated with NUC-3373 ± LV in Part 1 of NuTide:302 is shown below. Updated data on the clinical activity and safety of NUC-3373 will be presented. Clinical trial information: NCT03428958. Conclusions:NUC-3373 ± LV has shown clinical activity in heavily pre-treated CRC patients, including tumor shrinkage in a fluoropyrimidine-refractory patient. The safety profile of NUC-3373 ± LV is very encouraging: no neutropenia or hand-foot syndrome of any grade and no diarrhea or mucositis above Grade 2. NUC-3373 +LV is currently being dose escalated further in Part 1 and dosed with either oxaliplatin (NUFOX) or irinotecan (NUFIRI) in Part 2 of NuTide:302. [Table: see text]

scholarly journals Combining chloroquine with RAD001 inhibits tumor growth in a NEN mouse model

2018 ◽  
Vol 25 (6) ◽  
pp. 677-686 ◽  
Author(s):  
Shani Avniel-Polak ◽  
Gil Leibowitz ◽  
Victoria Doviner ◽  
David J Gross ◽  
Simona Grozinsky-Glasberg
Keyword(s):  
Mouse Model ◽  
Tumor Growth ◽  
Mtor Inhibitors ◽  
Degradation Pathway ◽  
Neuroendocrine Neoplasms ◽  
Histopathological Analysis ◽  
Anti Cancer ◽  
Subcutaneous Xenograft ◽  
Rheumatic Drug

Patients with neuroendocrine neoplasms (NENs) often require systemic treatment, which is frequently limited by the emergence of drug resistance. mTOR inhibitors (mTORi), such as RAD001 (everolimus), have been shown to inhibit neoplasm progression. mTORi stimulates autophagy, a degradation pathway that might promote the survival of neoplasm cells that are exposed to anti-cancer therapy. Chloroquine (CQ), a well-known anti-malarial and anti-rheumatic drug, suppresses autophagy. Based on our previous results, we hypothesized that CQ may enhance the anti-tumorigenic effects of mTORi by inhibiting autophagy and we aimed to examine the anti-tumorigenic effect of CQ, alone or in combination with RAD001. We established a NEN subcutaneous xenograft mouse model and evaluated the effect of the drugs on tumor growth, mTOR pathway, autophagy and apoptosis. CQ alone and in combination with RAD001 significantly decreased neoplasm volume. Histopathological analysis revealed that the combination of CQ and RAD001 markedly inhibited mTOR activity and neoplasm cell growth, along with accumulation of autophagosomes and increased apoptosis. In conclusion, CQ enhances the anti-tumorigenic effect of RAD001 in vivo by inhibiting autophagy. Clinical trials addressing the effects of CQ therapy on neoplasm progression in patients with NENs, mainly in those treated with mTORi, are warranted.

scholarly journals Development of Small-Molecule STING Activators for Cancer Immunotherapy

Biomedicines ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 33
Author(s):  
Hee Ra Jung ◽  
Seongman Jo ◽  
Min Jae Jeon ◽  
Hyelim Lee ◽  
Yeonjeong Chu ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Cyclic Gmp ◽  
Therapeutic Potential ◽  
Interferon Response ◽  
Type I ◽  
Anti Cancer ◽  
Cancer Agent ◽  
Sting Pathway

In cancer immunotherapy, the cyclic GMP–AMP synthase–stimulator of interferon genes (STING) pathway is an attractive target for switching the tumor immunophenotype from ‘cold’ to ‘hot’ through the activation of the type I interferon response. To develop a new chemical entity for STING activator to improve cyclic GMP-AMP (cGAMP)-induced innate immune response, we identified KAS-08 via the structural modification of DW2282, which was previously reported as an anti-cancer agent with an unknown mechanism. Further investigation revealed that direct STING binding or the enhanced phosphorylation of STING and downstream effectors were responsible for DW2282-or KAS-08-mediated STING activity. Furthermore, KAS-08 was validated as an effective STING pathway activator in vitro and in vivo. The synergistic effect of cGAMP-mediated immunity and efficient anti-cancer effects successfully demonstrated the therapeutic potential of KAS-08 for combination therapy in cancer treatment.

scholarly journals Berberine inhibits the proliferation of pancreatic cancer targeting pancreatic cancer stem cells

2021 ◽  
Author(s):  
Mengmeng Liu ◽  
Yue Pan ◽  
Xufeng Tao ◽  
Ning Li ◽  
Kun Li ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Effectiveness ◽  
The Novel ◽  
Migration Assay ◽  
Medicinal Value ◽  
Anti Cancer ◽  
Cancer Agent ◽  
Pancreatic Cancer Stem Cells

Abstract BackgroundPDAC is universally acknowledged to be one of the highest mortality rate of cancer-related deaths. PCSCs, regulated by EMT, could promote the proliferation of PDAC. Berberine with high medicinal value has usually been used as an anti-cancer agent. Hence the purpose of this study is to investigate the anti-cancer effect of berberine in PDAC. MethodsMTT assay was used to verify berberine inhibiting the proliferation of PDAC. Immunofluorescence staining, stem cell sphere, wound healing and transwell migration assay were demonstrated the anti-proliferation and anti-stemness of PCSCs in vitro . PANC-02 cells were injected in C57BL/6 mice to establish the orthotopic pancreatic-cancer model in vivo . H&E and Ki67 immunohistogical staining assay were used to evaluated the effect of berberine in PDAC in vivo. q-PCR and Western blot methods were applied to detect the expression of EMT procedure.ResultsIn this study, berberine has selective anti-cancer effect in PDAC in vitro . Moreover, berberine suppressed the proliferation and stemness of PCSCs in PDAC. In vivo , berberine reduced the tumor size and decreased the expression of Ki67 in orthotopic pancreatic-cancer pancreases. In addition, berberine inhibit the EMT signaling pathway both in vitro and in vivo . ConclusionsOur study indicates that berberine inhibit the proliferation of PDAC in vivo and vitro . The mechanism of anti-cancer effect on berberine may suppress the PCSCs through inhibiting EMT procedure. Therefore, berberine may be the novel antineoplastic drug with clinical effectiveness in PDAC. Keywords: Berberine, PDAC, PCSCs, EMT, berberine

Endometrial cancer: experimental models useful for studies on molecular aspects of endometrial cancer and carcinogenesis.

2003 ◽  
pp. 23-42 ◽  
Author(s):  
G Vollmer
Keyword(s):  
Endometrial Cancer ◽  
Tumor Cell ◽  
Cell Lines ◽  
Hormone Replacement ◽  
Endometrial Adenocarcinoma ◽  
Experimental Models ◽  
New Drugs ◽  
Tumor Cell Lines ◽  
Endometrial Cancers

There is definitely a need for the development of new drugs for the treatment and cure of endometrial cancer. In addition there are various new drugs or phyto-remedies under development which are intended for use in the treatment and prevention of breast cancer, for the treatment of menopausal symptoms and for hormone replacement therapy. The efficacy of novel drugs targeting steroid receptors in endometrial cancers has to be evaluated and the safety of other endocrine measures on endometrial cancers or on endometrial carcinogenesis has to be assessed. For these experimental purposes five main classes of experimental models are available: spontaneous endometrial tumorigenesis models in inbred animals (Donryu rats, DA/Han rats, BDII/Han rats), inoculation tumors from chunks of tumors (rat EnDA-tumor, human EnCa 101 tumor) or from inoculated tumor cell lines (rat RUCA-I cells, human Ishikawa and ECC-1 cells), developmental estrogenic exposure or chemical carcinogen exposure of CD-1 and ICR mice, transgenic approaches such as mice heterozygous regarding the tumor suppressor gene PTEN (pten(+/-)-mice) and endometrial tumor cell lines cultured under conditions promoting in vivo-like morphology and functions e.g. cell culture on reconstituted basement membrane. Although the number of models is comparatively small, most aspects related to functions of estrogenic or gestagenic substances are assessable, particularly if various experimental models are combined. Whereas models based on human endometrial adenocarcinoma cells are widely used, the properties and advantages of animal-derived models have mainly been ignored so far.

Establishment of Bioluminescence Imaging Based Leukemia In Vivo Model for Preclinical Testing

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4879-4879
Author(s):  
Myoung Woo Lee ◽  
Hye Jin Kim ◽  
Dae Seong Kim ◽  
Meong Hi Son ◽  
Soo Hyun Lee ◽  
...  
Keyword(s):  
Animal Model ◽  
Mouse Model ◽  
Drug Screening ◽  
Scid Mouse ◽  
Lymphoblastic Leukemia ◽  
Cancer Drug ◽  
Screening System ◽  
Bioluminescent Signal ◽  
Anti Cancer

Abstract Abstract 4879 Background. A hematological malignant animal model is an essential tool for evaluating efficacy of anti-cancer drugs and elucidating underlying mechanism of leukemogenesis. Intraperitoneal (IP) and intravenous (IV) xenograft of acute lymphoblastic leukemia (ALL) cells have limited capacity as in vivo anti-cancer drug screening system. Purpose. In this study, we aimed to establish an ALL animal model using NOD/SCID mouse and evaluate efficiency and sensitivity of the model as a preclinical drug screening system. Materials and Methods. Firefly luciferase (fLuc)-gene introduced ALL (ALL/fLuc) cell line and patient-originated ALL cells were transplanted into a tibia of NOD/SCID mouse. We conducted a comparative analysis of intra-bone marrow (IBMT) transplanted leukemia model with IP and IV transplantation of leukemic cells. Results. IBMT of ALL/fLuc cells effectively established a bioluminescent leukemia NOD/SCID mouse model. Upon comparison of IBMT model with IP and IV transplantation models, infusing identical number of ALL/fLuc cells into NOD/SCID mice resulted in IBMT model with evaluable bioluminescent signal, but not in IP and IV models. In IBMT model, bioluminescent signals of ALL/fLuc cells emitted from peripheral blood, tibia and infiltrated organs indicated that leukemia model was established. The changes in these signals' strength reflected dose-dependent cytotoxic effects of vincristine, which allowed leukemia model with evaluable bioluminescent signal to be utilized as a preclinical drug screening system. IBMT leukemia model was also established using primary ALL cells that can provide additional insights for the development of leukemia therapeutics. Conclusion. IBMT of ALL/fLuc cells enables development of leukemia mouse model with the greater bioluminescent sensitivity than IP and IV in NOD/SCID to evaluate candidate for development of anti-cancer drug. Disclosures: No relevant conflicts of interest to declare.

Phase IB trial redesign to test role of IL2 with anti-PSMA designer T cells to yield responses in advanced prostate cancer.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 70-70 ◽  
Author(s):  
Richard P. Junghans
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
T Cells ◽  
Metastatic Prostate Cancer ◽  
Immune Therapy ◽  
High Dose ◽  
Activated T Cells ◽  
Phase Ib ◽  
Cell Dose

70 Background: We created a chimeric antigen receptor (CAR) for prostate specific membrane antigen (PSMA). When expressed in patient T cells, these “designer T cells” specifically kill prostate cancer cells in vitro and in vivo in animal models (Ma et al. Prostate 2004:61:12-25). FDA approved a Phase I clinical trial. Methods: Patient T cells are retrovirally transduced and expanded. Patients undergo non-myeloablative (NMA) conditioning to create “hematologic space” into which designer T cells are infused for engraftment and improved in vivo efficacy. Patients are co-administered continuous infusion IL2. Patients are monitored for safety and response. Results: Five patients were treated, three at 10^9 and two at 10^10 cell dose levels with safety. Partial responses (PR) were seen in 2/5 patients (40%), with PSA suppressions of 50 and 70% over 1-2 months and PSA progression delay of 70 and 150 days. Yet these responses were observed only at the lowest T cell dose (10^9 cells) and not the higher tested dose (10^10 cells). Response correlated with plasma IL2 that was as much as 10-fold lower in non-responders vs responders. This low IL2 correlated in turn with high engrafted fractions of infused activated T cells. This prompted a hypothesis that infused activated T cells at high engrafted cell numbers absorbed out IL2 to a level too low to sustain dTc activation for effective tumor killing. A study redesign will test high dose IL2 (HDI) versus moderate dose IL2 (MDI) in Phase Ib/Pilot at 10^10 cell dose, then advancing to the maximum practical dose (MPD, 10^11 cells) of dTc under the optimal IL2 plan. Conclusions: A new approach to adoptive immune therapy in metastatic prostate cancer has been devised with encouraging early results. We postulate that adequate higher IL2 in vivo will allow the greater potency of higher dTc doses to be revealed, thereby potentially inducing PSA reductions of 100%, with durable remissions of metastatic prostate cancer that is refractory to all other treatments. Patients are being recruited. This clinical trial received funding from US Army/DOD and from Prostate Cancer Foundation for preclinical work.

BBI608-201GBM: A phase Ib/II clinical study of napabucasin (BBI608) in combination with temozolomide (TMZ) for adult patients with recurrent glioblastoma (GBM).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13525-e13525 ◽  
Author(s):  
Warren P. Mason ◽  
Paula de Robles ◽  
Laura Borodyansky ◽  
Matthew Hitron ◽  
Waldo Feliu Ortuzar ◽  
...  
Keyword(s):  
Recurrent Glioblastoma ◽  
Open Label ◽  
Cancer Stemness ◽  
Phase Ib ◽  
Anti Cancer ◽  
First Recurrence ◽  
Multi Center Study ◽  
Anti Tumor Activity

e13525 Background: Napabucasin, a first-in-class cancer stemness inhibitor in clinical development, suppresses cancer stemness by targeting STAT3-driven gene transcription. Pre-clinically, potent and broad-spectrum anti-cancer activity was observed in vitro and in vivo, alone and in combination with other agents. PK studies demonstrated napabucasin penetration in the murine orthotopic GBM model. Methods: A phase Ib/II open-label, multi-center study in pts with GBM at first recurrence who have not received bevacizumab, was performed to determine safety and preliminary activity of napabucasin administered orally at 480mg BID po in combination with TMZ 150mg/m²/day po; days 1 through 5 of each 28 day cycle, until disease progression or unacceptable toxicity. A 6-patient safety cohort was planned to evaluate the occurrence of DLT during the first 28 days of combination treatment with napabucasin and TMZ. 4 additional patients have been enrolled under the RP2D expansion phase. Results: 11 pts have been enrolled to date; no DLT was observed in the safety cohort and the RP2D of the combination is 480 mg BID for napabucasin. The safety profile was consistent with that of each agent as monotherapy and most common AEs included grade 1/2 diarrhea, nausea, abdominal cramps, and vomiting. Two patients requested to withdraw treatment due to concurrent conditions and AE s. 9 patients were evaluable by RANO; Disease Control Rate was observed in 5 patients (55.5%) of which 4 achieved PR (44.4%) and 1 achieved SD (11.1%). The Overall response rate was 44.4% in the evaluable patients. Conclusions: This phase Ib/II study demonstrated that napabucasin at 480 mg BID can be safely combined with temozolomide at full dose and showed encouraging anti-tumor activity in patients with recurrent Glioblastoma. Clinical trial information: NCT02315534. [Table: see text]

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