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Papers by Jose Alfon

Frontiers in Oncology

BackgroundGlioblastoma multiforme (GBM) is the most malignant adult brain tumor. Current standard... more BackgroundGlioblastoma multiforme (GBM) is the most malignant adult brain tumor. Current standard of care treatments have very limited efficacy, being the patients´ overall survival 14 months and the 2-year survival rate less than 10%. Therefore, the treatment of GBM is an urgent unmet clinical need.MethodsThe aim of this study was to investigate in vitro and in vivo the potential of ABTL0812, an oral anticancer compound currently in phase II clinical stage, as a novel therapy for GBM.ResultsWe showed that ABTL0812 inhibits cell proliferation in a wide panel of GBM cell lines and patient-derived glioblastoma stem cells (GSCs) with half maximal inhibitory concentrations (IC50s) ranging from 15.2 µM to 46.9 µM. Additionally, ABTL0812 decreased GSCs neurosphere formation. GBM cells aggressiveness is associated with a trans-differentiation process towards a less differentiated phenotype known as proneural to mesenchymal transition (PMT). ABTL0812 was shown to revert PMT and induce cell ...

Cancer Research, 2021

ABTL0812 induces cytotoxic autophagy in cancer cells through the combination of ER stress inducti... more ABTL0812 induces cytotoxic autophagy in cancer cells through the combination of ER stress induction and Akt/mTOR blockade. ABTL0812 induces ER stress mediated activation of JNK-Jun pathway and inhibition of the STAT3-IL10 axis in cancer and immune cells in vitro and induces ER stress markers TRIB3 and CHOP in white blood cells of patients with no toxic effects and showing clinical efficacy in Phase 2 trial in combination with chemotherapy vs chemotherapy alone (historical data). In primary and immortalized monocytes-derived macrophages in vitro, ABTL0812 promoted M1 phenotypes potentiating IL-1β and TNFα expression and suppressed M2 phenotypes by decreasing IL-10 expression, as detected by RT-qPCR. Additionally, ABTL0812 inhibited the release of immunosuppressive chemokines (CXCL5, CCL5, CCL8) detected by protein array. In human primary T cells cultured in vitro, ABTL0812 decreased PD1 surface expression in non-activated and activated CD4 and CD8 cells detected by flow cytometry. In...

Cancer Communications, 2022

ABTL0812 enhances antitumor effect of paclitaxel and reverts chemoresistance in triple-negative b... more ABTL0812 enhances antitumor effect of paclitaxel and reverts chemoresistance in triple-negative breast cancer models Dear Editor, Triple-negative breast cancer (TNBC) accounts for 20% of all breast carcinomas and lacks a validated targeted therapy; thus, currently, cytotoxic chemotherapy is the treatment of choice [1]. Compared with other breast cancer types, patients with TNBC are younger, have larger tumors, a higher risk of metastasis, and a higher rate of recurrence [2]. Among all the subtypes described by Lehmann et al. [3], mesenchymal-like and mesenchymal stem-like (MSL) subtypes had the lowest 5-year distant metastasis-free survival rates. Therefore, the aggressiveness and poor prognosis of TNBC call for new and more effective therapies. ABTL0812 is a novel first-in-class anticancer agent. It was initially selected for preclinical development based on its anti-proliferative effect on different human cancer cell lines and its safety profile in animal models as both single therapy and in combination with chemotherapy [4-8]. A first-inhuman phase I clinical trial with ABTL0812 was successfully completed, showing a high safety profile and signs of efficacy in patients with advanced solid tumors who had received ABTL0812 orally after several chemotherapy lines (NCT02201823). Based on these findings, a phase I/IIa clinical trial was performed whereby ABTL0812 was administered as first-line therapy in combination with paclitaxel and carboplatin in patients with advanced/recurrent endometrial and metastatic squamous non-small cell lung cancers (NSCLC). The trial results observed improved efficacy without increasing toxicities, compared to chemotherapy alone (NCT03366480).

European Journal of Cancer, 2021

BACKGROUND ABTL0812 is an autophagy inducer that promotes cancer cell death by activation of cyto... more BACKGROUND ABTL0812 is an autophagy inducer that promotes cancer cell death by activation of cytotoxic autophagy selectively in tumour cells. ABTL0812 induces endoplasmic reticulum stress and blocks the Akt-mTOR axis; both actions converge to activate a robust and sustained autophagy leading to cancer cell death. Preclinical data supported the initiation of clinical trials in patients with cancer. PATIENTS AND METHODS This first-in-human trial consisted of an escalation phase (3 + 3 design), followed by an expansion phase, to assess safety and tolerability of ABTL0812. Secondary objectives were determining the recommended phase II dose (RP2D), clinical antitumour activity, pharmacokinetics (PK) and pharmacodynamics (PD). RESULTS A total of 29 patients were enrolled and treated; fifteen patients were treated in four escalation dosing cohorts (ranging from 500 mg once a day to 2000 mg twice a day) and fourteen in the expansion phase (dosed with 1300 mg three times a day). No maximum tolerated dose was attained, and RP2D was determined by PK/PD modelling. Most drug-related adverse events were gastrointestinal grade I-II. Correlation between drug levels and pAkt/Akt ratio was found. Two cases of long-term (>1 year) stable disease were observed. CONCLUSIONS ABTL0812 is safe and has an acceptable tolerability profile, allowing a long-term oral dosing. RP2D of 1300 mg three times a day was determined according to PK/PD modelling, and preliminary antitumour efficacy was observed. CLINICAL TRIAL REGISTRATION NUMBER NCT02201823.

Pharmaceutical Research, 2004

Chemotherapy with high-dose methotrexate (HD-MTX) is often associated with acute neurotoxicity. W... more Chemotherapy with high-dose methotrexate (HD-MTX) is often associated with acute neurotoxicity. We determined whether the altered neuronal function after HD-MTX [such as the reduced regional cerebral metabolic glucose rate (rCMRGlc) and slow electroencephalographic pattern] affects the sensitivity of the CNS to centrally acting drugs: the depressant phenobarbital, which reduces rCMRGlc, and the analeptic agent pentylenetetrazol (PTZ), which elevates rCMRGlc. Adult male Sabra rats received an i.v. infusion of MTX, 0.51 mg/min, to induce neurotoxicity or saline solution for 24 hr. Subsequently, MTX-treated and control groups were infused in one experiment with phenobarbital until loss of the righting reflex and in the second experiment with PTZ until the onset of maximal seizures. HD-MTX did not affect the infused hypnotic dose or serum, brain, and cerebrospinal fluid concentrations of phenobarbital at the onset of anesthesia. The convulsive dose and PTZ concentrations in the serum an...

Cell Death & Disease, 2020

Neuroblastoma is the leading cause of cancer death in children aged 1 to 4 years. Particularly, f... more Neuroblastoma is the leading cause of cancer death in children aged 1 to 4 years. Particularly, five-year overall survival for high-risk neuroblastoma is below 50% with no curative options when refractory or relapsed. Most of current therapies target cell division and proliferation, thereby inducing DNA damage and programmed cell death. However, aggressive tumours often present alterations of these processes and are resistant to therapy. Therefore, exploring alternative pathways to induce tumour cell death will provide new therapeutic opportunities for these patients. In this study we aimed at testing the therapeutic potential of ABTL0812, a novel anticancer drug that induces cytotoxic autophagy to eliminate cancer cells, which is currently in phase II clinical trials of adult tumours. Here, we show that ABTL0812 impaired the viability of clinical representative neuroblastoma cell lines regardless of genetic alterations associated to bad prognosis and resistance to therapy. Oral adm...

Annals of Oncology, 2020

Background: Mirvetuximab soravtansine (MIRV) is an ADC comprising a FRa-binding antibody, linked ... more Background: Mirvetuximab soravtansine (MIRV) is an ADC comprising a FRa-binding antibody, linked to the tubulin-disrupting maytansinoid DM4. MIRV has promising single agent activity in FRa-positive epithelial ovarian cancer (EOC), at 6 mg/kg, based on adjusted ideal body weight (AIBW) IV every (q) 21 days. Clinical data in other FRapositive solid tumors has been limited. This study is evaluating MIRV and G in recurrent EOC, EC and triple negative breast cancer (TNBC). The recommended phase II dose (RP2D) reported at ASCO 2019, was established at DL3 (MIRV 6 mg/kg AIBW IV, day 1 and G 800 mg/m2 IV, d1, 8) q21 days. Here we report the results in the EC cohort treated at the RP2D. Methods: Pts with FRa-positive EC with 2 prior chemotherapy (CT) regimens are eligible. FRa positivity by immunohistochemistry was initially defined as 25% of cells with PS2+ staining intensity (low to high FRa levels) and was subsequently revised to 50% of cells with PS2+ (medium/high FRa levels, with high defined as 75% of cells with PS2+). The expansion cohort of 12 pts with FRa-positive EC treated at the RP2D pre-specified that 2 responders are required to declare the combination promising. Results: From October 2017 to May 2020, 55 EC pts underwent FRa screening, with 4 results pending. Out of 51 EC pts with results, 12 pts (23.5%) have medium/high FRa levels with 5 pts (9.8%) have low FRa level. 5 EC pts were treated at the RP2D (1 too early and 4 evaluable for response of which 1 pt had medium FRa and 3 pts had low FRa). 2 of the 4 evaluable EC pts at the RP2D achieved a partial response (PR). 1 PR was observed on cycle 7 (the only medium FRa level pt) and the second PR was on cycle 3. One pt. had SD after 4 cycles and remains on treatment, and 1 pt progressed in the 1 st cycle. Grade (G) 3-4 adverse events (AEs) in the 4 evaluable pts treated at the RP2D were infrequent and included: Gr 4 lymphopenia (1 pt), Gr 3 ANC/WBC/PLT (1 pt), and Gr 3 HTN and lymphopenia (1pt). Conclusions: The combination of MIRV with G has promising clinical activity in FRapositive EC. The regimen is tolerable with the expected treatment related AEs of these agents. Clinical trial identification: NCT02996825.

Cancer Research, 2020

ABTL0812 is a first-in-class small molecule with anticancer activity currently in Phase 2a clinic... more ABTL0812 is a first-in-class small molecule with anticancer activity currently in Phase 2a clinical evaluation in patients with advanced endometrial and squamous NSCLC. We have previously described that ABTL0812 induces TRIB3 pseudokinase expression, resulting in inhibition of the Akt-mTORC1 axis and autophagy-mediated cancer cell death. However, classical PI3K/Akt/mTOR inhibitors do not induce an autophagy as strong as ABTL0812 does, therefore we aimed to further elucidate the molecular mechanism responsible for the cytotoxic autophagy which causes ABTL0812 anticancer activity. ABTL0812 induced UPR hallmarks ATF4, CHOP and TRIB3 in vitro in lung, endometrial and pancreatic cancer cell lines, as well as in non-tumor cells. Nevertheless, therapeutic concentrations of ABTL0812 did not induce cytotoxic autophagy in non-tumor cells. Furthermore, genetic or pharmacological inhibition of the UPR resulted in impaired ABTL0812 cytotoxicity in cancer cells. Expression of UPR markers (ATF4, C...

Journal of Clinical Oncology, 2013

e13526 Background: We have previously described that ABTL0812 has oral anticancer properties. The... more e13526 Background: We have previously described that ABTL0812 has oral anticancer properties. The action is exerted through a mechanism of action involving the inhibition of mTORC1 and mTORC2 (mammalian target of rapamycin) pathways and dihydrofolate reductase (DHFR) expression. Administration of ABTL0812 reduced tumor volume similarly or more than standards of care (SOC) in A549 or MiaPaca2 xenografts in mice. Moreover, a 28-day rat toxicity study has shown very low toxicity (NOAEL=500 mg/Kg) good bioavailability and pharmacokinetic linearity, suggesting a broad therapeutic window. A FiM phase I clinical trial in patients with advanced cancer is scheduled to start in June 2013. Methods: Cellular assays were performed in A549 lung adenocarcinoma, and MiaPaca-2 pancreatic carcinoma cells. Cell proliferation was carried out by bromodeoxyuridine (BrdU) incorporation, cell viability by MTT, and protein expression and phosphorylation by immunoblotting. Cellular apoptosis was assessed bot...

International Journal of Cancer, 2020

Around 40% of newly diagnosed lung cancer patients are Stage IV, where the improvement of surviva... more Around 40% of newly diagnosed lung cancer patients are Stage IV, where the improvement of survival and reduction of disease‐related adverse events is the main goal for oncologists. In this scenario, we present preclinical evidence supporting the use of ABTL0812 in combination with chemotherapy for treating advanced and metastatic Nonsmall cell lung adenocarcinomas (NSCLC) and squamous carcinomas. ABTL0812 is a new chemical entity, currently in Phase 1b/2a clinical trial for advanced squamous NSCLC in combination with paclitaxel and carboplatin (P/C), after successfully completing the first‐in‐human trial where it showed an excellent safety profile and signs of efficacy. We show here that ABTL0812 inhibits Akt/mTOR axis by inducing the overexpression of TRIB3 and activating autophagy in lung squamous carcinoma cell lines. Furthermore, treatment with ABTL0812 also induces AMPK activation and ROS accumulation. Moreover, combination of ABTL0812 with chemotherapy markedly increases the t...

Journal of Clinical Oncology, 2017

e17070 Background: ABTL0812 is a first-in-class anti-cancer agent with a unique mechanism of acti... more 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. Res...

Journal of Clinical Oncology, 2015

2585 Background: ABTL0812 is a novel drug with reported preclinical activity in several tumor typ... more 2585 Background: ABTL0812 is a novel drug with reported preclinical activity in several tumor types. In vitro and in vivo assays have shown that ABTL0812 is an inhibitor of the Akt/mTOR pathway by ...

Gynecologic Oncology, 2019

• ABTL0812 is a small molecule inhibitor and is an effective therapeutic option for high-risk end... more • ABTL0812 is a small molecule inhibitor and is an effective therapeutic option for high-risk endometrial cancer patients. • ABTL0812 acts by inducing TRIB3 expression, inhibiting the PI3K/AKT/ mTOR axis, and promoting autophagy cell death. • In preclinical models, ABTL0812 kills endometrial cancer cells but not healthy endometrial cells. • ABTL0812 stops hyperplasic lesions to progress to cancer.

Thrombosis and Haemostasis, 1999

SummaryHMG-CoA reductase inhibitors (statins) are effective in primary and secondary prevention o... more SummaryHMG-CoA reductase inhibitors (statins) are effective in primary and secondary prevention of coronary heart disease. The mechanism of action is mainly attributed to their plasma cholesterol lowering activity, although additional effects have been suggested. Our objective was to study whether atorvastatin and simvastatin exhibited an inhibitory effect on platelet deposition onto a triggering damaged vessel wall in addition to an antiatherosclerotic effect in the dyslipemic rabbit model. Statins were administered at identical doses of 2.5 mg/kg/day with a hyperlipidemic diet during 10 weeks. Both drugs similarly lowered total cholesterol and, moderately, triglycerides. Mural platelet deposition on damaged vessel wall placed in an ex-vivo flow perfusion system was reduced in atorvastatin treated animals (39.7 ± 6.2 × 106 PLT/cm2) vs. controls (94.8 ± 15.9 × 106 PLT/cm2, p <0.02). Simvastatin reduced aortic fatty streak surface coverage (31,7 ± 5.3%) vs. controls (47.9 ± 4.1%, ...

Molecular Cancer Therapeutics, 2015

Background: ABTL0812 is a first-in-class antitumor drug whose mechanism of action relies on the i... more Background: ABTL0812 is a first-in-class antitumor drug whose mechanism of action relies on the inhibition of PI3K/Akt/mTOR (PAM) pathway by upregulation of TRIB3 levels, an endogenous inhibitor of Akt activity that prevents Akt phosphorylation. Preclinical studies showed good efficacy of ABTL0812 in xenograft models with high safety margin. Here we describe the First-in-Human (FiH) Phase I/Ib clinical trial of ABTL0812 in patients with advanced solid tumors (NCT02201823). Methods: ABTL0812 was dosed daily, by the oral route, in 28-day cycles. The study included a 4-cohort dose escalation, in a 3+3 dose escalating design, followed by an expansion cohort. The trial objectives were to determine safety and tolerability, to evaluate signs of efficacy, to determine drug pharmacokinetics (PK) in plasma and to analyze inhibition of Akt phosphorylation in platelets by MSD® as pharmacodynamic (PD) biomarker. Pretreatment tumor biopsies were analyzed by next generation sequencing to identify ...

Cancer Research, 2015

Background: ABTL0812 is a first-in-class orally administered compound currently in Phase I/Ib Fir... more Background: ABTL0812 is a first-in-class orally administered compound currently in Phase I/Ib First in Human Clinical Trial in patients with advanced solid tumors (NCT02201823). ABTL0812 has cytotoxic effect on a wide range of human tumor cell lines, including those which have become resistant to standard therapy. We hereby dissect the anti-tumor activity of ABTL0812, which relies on a novel mechanism of action that promotes inhibition of the Akt/mTOR axis in cancer cells. Material & methods: ABTL0812 molecular targets were identified by in silico analysis, comparing ABTL0812 chemical structure against a database including more than one million receptor-ligand interaction data. Functional relevance of the targets was confirmed biochemically and pharmacologically. ABTL0812 mechanism of action was established using human lung and pancreatic tumor cells, MEF KO cells, as well as tumor xenografts. Results: In silico screening showed that ABTL0812 binds four targets which regulate tumor ...

Zeitschrift für Kardiologie, 1995

PTCA is a well established intervention to reduce the severity of atherosclerotic coronary stenos... more PTCA is a well established intervention to reduce the severity of atherosclerotic coronary stenosis. In spite of a primary success rate of 90 - 95%, late restenosis occurs in 30 - 50% of patients within 3/6 months of the procedure. Angioplasty in swine induces similar events to those found in humans, thus providing a model for studying strategies for intervention. Blood interaction to the damaged vessel wall occurs with reperfusion after the intervention. Therefore, the in vivo characterization of the interaction of cellular elements (platelets and white cells) and blood proteins with the exposed vascular cells in the vessel wall post-angioplasty may be necessary to identify early triggers of restenosis. Angioplasty was performed simultaneously in the coronary and carotid arteries of swine by fluoroscopy assisted standard techniques. Angiography was performed acutely post-dilatation and residual lumen diameter evaluated. Dilated vessels from 30 min to 6 h postintervention were proce...

A31. OPTIMIZING THERAPEUTIC STRATEGIES IN AIRWAYS DISEASE, 2011