Ponatinib, Lestaurtinib and mTOR/PI3K inhibitors are promising repurposing candidates against Entamoeba histolytica

2021 ◽  
Author(s):  
Monica M. Kangussu-Marcolino ◽  
Upinder Singh
Keyword(s):  
Entamoeba Histolytica ◽  
Current Treatment ◽  
Clinical Development ◽  
New Drugs ◽  
Phase Iii ◽  
Significant Advance ◽  
Pi3k Inhibitors ◽  
Treatment Regimens ◽  
Clinical Resistance ◽  
Tk Inhibitors

Dysentery caused by Entamoeba histolytica affects millions of people annually. Current treatment regimens are based on metronidazole to treat invasive parasites combined with paromomycin for luminal parasites. Issues with treatment include significant side effects, inability to easily treat breastfeeding and pregnant women, the use of two sequential agents, and concern that all therapy is based on nitroimidazole agents with no alternatives if clinical resistance emerges. Thus, the need for new drugs against amebiasis is urgent. To identify new therapeutic candidates, we screened the ReFRAME library (11,948 compounds assembled for Repurposing, Focused Rescue, and Accelerated Medchem) against E. histolytica trophozoites. We identified 159 hits in the primary screen at 10 μM and 46 compounds were confirmed in secondary assays. Overall, 26 were selected as priority molecules for further investigation including 6 FDA approved, 5 orphan designation, and 15 which are currently in clinical trials (3 phase III, 7 phase II and 5 phase I). We found that all 26 compounds are active against metronidazole resistant E. histolytica and 24 are able to block parasite recrudescence after drug removal. Additionally, 14 are able to inhibit encystation and 2 (lestaurtinib and LY-2874455) are active against mature cysts. Two classes of compounds are most interesting for further investigations: the Bcr-Abl TK inhibitors, with the ponatinib (EC 50 0.39) as most potent and mTOR or PI3K inhibitors with 8 compounds in clinical development, of which 4 have nanomolar potency. Overall, these are promising candidates and represent a significant advance for drug development against E. histolytica .

From sequential to combination and personalised therapy in lupus nephritis: moving towards a paradigm shift?

2021 ◽  
pp. annrheumdis-2021-221270
Author(s):  
Ioannis Parodis ◽  
Frederic A Houssiau
Keyword(s):  
Lupus Nephritis ◽  
Maintenance Phase ◽  
Tissue Level ◽  
Current Treatment ◽  
Phase Iii ◽  
Treat To Target ◽  
Treatment Regimens ◽  
Treatment Paradigm ◽  
Therapeutic Decision Making ◽  
The Right

The current treatment paradigm in lupus nephritis consists of an initial phase aimed at inducing remission and a subsequent remission maintenance phase. With this so-called sequential treatment approach, complete renal response is achieved in a disappointing proportion of 20–30% of the patients within 6–12 months, and 5–20% develop end-stage kidney disease within 10 years. Treat-to-target approaches are detained owing to uncertainty as to whether the target should be determined based on clinical, histopathological, or immunopathological features. Until reliable non-invasive biomarkers exist, tissue-based evaluation remains the gold standard, necessitating repeat kidney biopsies for treatment evaluation and therapeutic decision-making. In this viewpoint, we discuss the pros and cons of voclosporin and belimumab as add-on agents to standard therapy, the first drugs to be licenced for lupus nephritis after recent successful randomised phase III clinical trials. We also discuss the prospect of obinutuzumab and anifrolumab, also on top of standard immunosuppression, currently tested in phase III trials after initial auspicious signals. Undoubtably, the treatment landscape in lupus nephritis is changing, with combination treatment regimens challenging the sequential concept. Meanwhile, the enrichment of the treatment armamentarium shifts the need from lack of therapies to the challenge of how to select the right treatment for the right patient. This has to be addressed in biomarker surveys along with tissue-level mapping of inflammatory phenotypes, which will ultimately lead to person-centred therapeutic approaches. After many years of trial failures, we may now anticipate a heartening future for patients with lupus nephritis.

New Drugs and Treatment Regimens

2013 ◽  
Vol 9 (3) ◽  
pp. 200-210 ◽  
Author(s):  
Derek Sloan ◽  
Geraint Davies ◽  
Saye Khoo
Keyword(s):  
New Drugs ◽  
Treatment Regimens

scholarly journals MRD-Based Therapeutic Decisions in Genetically Defined Subsets of Adolescents and Young Adult Philadelphia-Negative ALL

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2108
Author(s):  
Manuela Tosi ◽  
Orietta Spinelli ◽  
Matteo Leoncin ◽  
Roberta Cavagna ◽  
Chiara Pavoni ◽  
...  
Keyword(s):  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Philadelphia Chromosome ◽  
Current Treatment ◽  
New Drugs ◽  
Term Survival ◽  
Therapeutic Decisions ◽  
Key Factor ◽  
Combined Strategy

In many clinical studies published over the past 20 years, adolescents and young adults (AYA) with Philadelphia chromosome negative acute lymphoblastic leukemia (Ph− ALL) were considered as a rather homogeneous clinico-prognostic group of patients suitable to receive intensive pediatric-like regimens with an improved outcome compared with the use of traditional adult ALL protocols. The AYA group was defined in most studies by an age range of 18–40 years, with some exceptions (up to 45 years). The experience collected in pediatric ALL with the study of post-induction minimal residual disease (MRD) was rapidly duplicated in AYA ALL, making MRD a widely accepted key factor for risk stratification and risk-oriented therapy with or without allogeneic stem cell transplantation and experimental new drugs for patients with MRD detectable after highly intensive chemotherapy. This combined strategy has resulted in long-term survival rates of AYA patients of 60–80%. The present review examines the evidence for MRD-guided therapies in AYA’s Ph− ALL, provides a critical appraisal of current treatment pitfalls and illustrates the ways of achieving further therapeutic improvement according to the massive knowledge recently generated in the field of ALL biology and MRD/risk/subset-specific therapy

scholarly journals AB0332 IMMUNOSUPPRESSIVE AND IMMONOMODULATING AGENTS IN RHEUMATOID ARTHRITIS: A SYSTEMATIC REVIEW OF CLINICAL TRIALS AND THEIR CURRENT DEVELOPMENT STAGE

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1464.1-1465
Author(s):  
J. Blaess ◽  
J. Walther ◽  
J. E. Gottenberg ◽  
J. Sibilia ◽  
L. Arnaud ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Systematic Review ◽  
B Cells ◽  
Phase I ◽  
Phase Ii ◽  
Clinical Development ◽  
Phase Iii ◽  
Jak Inhibitors ◽  
Exclusion Criteria ◽  
Immunomodulating Drugs

Background:Rheumatoid arthritis (RA) is the most frequent chronic inflammatory diseases with an incidence of 0.5% to 1%. Therapeutic arsenal of RA has continuously expanded in recent years with the recent therapeutic progress with the arrival of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), biological (bDMARDs) and targeted synthetic (tsDMARDs), JAK inhibitors. However, there are still some unmet needs for patients who do not achieve remission and who continue to worsen despite treatments. Of note, only approximately 40% of patients are ACR70 responders, in most randomized controlled trials. For these patients, finding new therapeutic avenues is challenging.Objectives:The objective of our study was to analyze the whole pipeline of immunosuppressive and immunomodulating drugs evaluated in RA and describe their mechanisms of action and stage of clinical development.Methods:We conducted a systematic review of all drug therapies in clinical development in RA in 17 databases of international clinical trials. Inclusion criterion: study from one of the databases using the keywords “Rheumatoid arthritis” (search date: June 1, 2019). Exclusion criteria: non-drug trials, trials not related to RA or duplicates. We also excluded dietary regimen or supplementations, cellular therapies, NSAIDs, glucorticoids or their derivatives and non-immunosuppressive or non-immunomodulating drugs. For each csDMARD, bDMARD and tsDMARD, we considered the study at the most advanced stage. For bDMARDs, we did not take into account biosimilars.Results:The research identified 4652 trials, of which 242 for 243 molecules met the inclusion and exclusion criteria. The developed molecules belong to csDMARDs (n=21), bDMARDs (n=117), tsDMARDs (n=105).Among the 21 csDMARDs molecules: 8 (38%) has been withdrawn, 4 (19%) are already labelled in RA (hydroxychloroquine, leflunomide, methotrexate and sulfasalazine) and 9 (43%) are in development: 1 (11%) is in phase I/II, 5 (56%) in phase II, 3 (33%) in phase IV.Among the 117 bDMARDs molecules: 69 (59%) has been withdrawn, 9 (8%) are labeled in RA (abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, sarilumab, tocilizumab) and 39 (33%) are in development: 9 (23%) in phase I, 3 (8%) in phase I/II, 21 (54%) in phase II, 5 (12%) are in phase III, 1 (3%) in phase IV. bDMARDs currently under development target B cells (n=4), T cells (n=2), T/B cells costimulation (n=2),TNF alpha (n=2), Interleukine 1 or his receptor (n=3), Interleukine 6 or his receptor (n=7), Interleukine 17 (n=4), Interleukine 23 (n=1), GM-CSF (n=1), other cytokines or chemokines (n=5), integrins or adhesion proteins (n=3), interferon receptor (n=1) and various other targets (n=4).Among the 105 tsDMARDs molecules: 64 (61%) has been withdrawn, 6 (6%) JAK inhibitors, have just been or will probably soon be labelled (baricitinib, filgotinib, peficitinib, tofacitinib and upadacitinib), 35 (33%) are in development: 8 (24%) in phase I, 26 (74%) in phase II, 1 (3%) in phase III and. tsDMARDs currently under development target tyrosine kinase (n=12), janus kinase (JAK) (n=3), sphingosine phostate (n=3), PI3K pathway (n=1), phosphodiesterase-4 (n=3) B cells signaling pathways (n=3) and various other targets (n=10).Conclusion:A total of 242 therapeutic trials involving 243 molecules have been or are being evaluated in RA. This development does not always lead to new treatments since 141 (58%) have already been withdrawn. Hopefully, some of the currently evaluated drugs will contribute to improve the therapeutic management of RA patients, requiring a greater personalization of therapeutic strategies, both in the choice of molecules and their place in therapeutic sequences.Disclosure of Interests:Julien Blaess: None declared, Julia Walther: None declared, Jacques-Eric Gottenberg Grant/research support from: BMS, Pfizer, Consultant of: BMS, Sanofi-Genzyme, UCB, Speakers bureau: Abbvie, Eli Lilly and Co., Roche, Sanofi-Genzyme, UCB, Jean Sibilia: None declared, Laurent Arnaud: None declared, Renaud FELTEN: None declared

scholarly journals The role of idecabtagene vicleucel in patients with heavily pretreated refractory multiple myeloma

2021 ◽  
Vol 12 ◽  
pp. 204062072110196
Author(s):  
Albert Oriol ◽  
Laura Abril ◽  
Anna Torrent ◽  
Gladys Ibarra ◽  
Josep-Maria Ribera
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Safety Profile ◽  
Proteasome Inhibitors ◽  
Clinical Development ◽  
Phase Iii ◽  
Acceptable Safety Profile ◽  
Refractory Multiple Myeloma ◽  
High Risk Patients ◽  
Risk Patients

The development of several treatment options over the last 2 decades has led to a notable improvement in the survival of patients with multiple myeloma. Despite these advances, the disease remains incurable for most patients. Moreover, standard combinations of alkylating agents, immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies targeting CD38 and corticoids are exhausted relatively fast in a proportion of high-risk patients. Such high-risk patients account for over 20% of cases and currently represent a major unmet medical need. The challenge of drug resistance requires the development of highly active new agents with a radically different mechanism of action. Several immunotherapeutic modalities, including antibody–drug conjugates and T-cell engagers, appear to be promising choices for patients who develop resistance to standard combinations. Chimeric antigen-receptor-modified T cells (CAR-Ts) targeting B-cell maturation antigen have demonstrated encouraging efficacy and an acceptable safety profile compared with alternative options. Multiple CAR-Ts are in early stages of clinical development, but the first phase III trials with CAR-Ts are ongoing for two of them. After the recent publication of the results of a phase II trial confirming a notable efficacy and acceptable safety profile, idecabtagene vicleucel is the first CAR-T to gain regulatory US Food and Drug Administration approval to treat refractory multiple myeloma patients who have already been exposed to antibodies against CD38, proteasome inhibitors, and immunomodulatory agents and who are refractory to the last therapy. Here, we will discuss the preclinical and clinical development of idecabtagene vicleucel and its future role in the changing treatment landscape of relapsed and refractory multiple myeloma.

scholarly journals Icaritin promotes apoptosis and inhibits proliferation by down-regulating AFP gene expression in hepatocellular carcinoma

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Hui Li ◽  
Yujuan Liu ◽  
Wei Jiang ◽  
Junhui Xue ◽  
Yuning Cheng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Cellular Proliferation ◽  
Chinese Herb ◽  
New Drugs ◽  
Phase Iii ◽  
P53 Expression ◽  
Expression Levels ◽  
Cellular Apoptosis ◽  
Afp Promoter

Abstract Background Icaritin, an active ingredient of the Chinese herb Epimedium, plays an anti-tumor role in liver cancer by inhibiting the proliferation of hepatocellular cells and promoting their apoptosis. In China, phase II and a large phase III clinical trial of icaritin reagent for the treatment of hepatocellular cancer is under-going, but the specific mechanism of icaritin action was unclear. Alpha-fetoprotein (AFP), an oncofetal protein, produced in the healthy fetal liver and yolk sac. Intracellular AFP promoted cellular proliferation and inhibited cellular apoptosis in hepatocellular carcinoma (HCC). The study was aimed to investigate the effect of icaritin on HCC through p53/AFP pathway. Methods Real-time RT PCR and western blot were used to detect p53 and AFP expression levels in HCC cells treated with icaritin. The mechanism of icaritin affecting p53 expression was verified by ubiquitination experiment, and the binding activity of icaritin on p53 in AFP promoter region was verified by luciferase experiment. EdU, MTT and flow cytometry were used to determine whether icaritin affected HCC cellular proliferation and apoptosis through p53/ AFP pathway. Expression levels of p53 and AFP in xenograft mouse model were determined by western blotting. Results Our results showed icaritin inhibited AFP expression at mRNA and protein level. AFP was also identified as the target gene of the p53 transcription factor. Icaritin abrogated murine double minute (Mdm) 2-mediated p53 ubiquitination degradation to improve the stability of p53. Up-regulated p53 protein levels then transcriptionally inhibited the AFP promoter. Icaritin-mediated decrease of AFP through Mdm2/p53 pathways inhibited HCC cellular proliferation and promoted HCC cellular apoptosis. Conclusion Our findings revealed the mechanism of icaritin in promoting apoptosis and inhibiting proliferation in liver cancer cells. The regulatory mechanism of icaritin in AFP protein down-regulation provides a theoretical and experimental basis for further research into new drugs for the treatment of liver cancer.

scholarly journals Benznidazole Treatment: Time- and Dose-Dependence Varies with the Trypanosoma cruzi Strain

Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 729
Author(s):  
Kátia da Silva Fonseca ◽  
Luísa Perin ◽  
Nívia Carolina Nogueira de Paiva ◽  
Beatriz Cristiane da Silva ◽  
Thays Helena Chaves Duarte ◽  
...  
Keyword(s):  
Treatment Adherence ◽  
Treatment Efficacy ◽  
Treatment Time ◽  
Standard Dose ◽  
Acute Infection ◽  
Chronic Phase ◽  
Disease Status ◽  
Dose Dependence ◽  
New Drugs ◽  
Treatment Regimens

As the development of new drugs for Chagas disease is not a priority due to its neglected disease status, an option for increasing treatment adherence is to explore alternative treatment regimens, which may decrease the incidence of side effects. Therefore, we evaluated the efficacy of different therapeutic schemes with benznidazole (BNZ) on the acute and chronic phases of the disease, using mice infected with strains that have different BNZ susceptibilities. Our results show that the groups of animals infected by VL-10 strain, when treated in the chronic phase with a lower dose of BNZ for a longer period of time (40 mg/kg/day for 40 days) presented better treatment efficacy than with the standard protocol (100 mg/kg/day for 20 days) although the best result in the treatment of the animals infected by the VL-10 strain was with100 mg/kg/day for 40 days. In the acute infection by the Y and VL-10 strains of T. cruzi, the treatment with a standard dose, but with a longer time of treatment (100 mg/kg/day for 40 days) presented the best results. Given these data, our results indicate that for BNZ, the theory of dose and time proportionality does not apply to the phases of infection.

scholarly journals Cabozantinib for the Management of Metastatic Clear Cell Renal Cell Carcinoma

2018 ◽  
Vol 5 (4) ◽  
pp. 1-5 ◽  
Author(s):  
Sharon Del Vecchio ◽  
Robert J Ellis
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Current Treatment ◽  
Phase Iii ◽  
Solid Organ ◽  
Cell Renal Cell Carcinoma ◽  
Randomised Controlled

Cabozantinib is a multi-tyrosine kinase inhibitor used for the treatment of various solid-organ tumours. It was recently approved as a first- and second-line therapeutic for the management of advanced/metastatic renal cell carcinoma based on the results of two randomised controlled trials. The phase III METEOR trial compared cabozantinib against everolimus as a second- or greater line therapy and found benefits in progression-free and overall survival, and the phase II CABOSUN trial compared cabozantinib against sunitinib as a first-line therapeutic and found benefits in terms of progression-free survival. This review briefly summarises how cabozantinib fits into current treatment paradigms for the management of advanced renal cell carcinoma.

scholarly journals DERN CONTROL POINT INHIBITORS AND THEIR POSSIBILITIES FOR THE THERAPY OF METASTATIC UROTELIAL CANCER

2020 ◽  
Vol 6 (5(74)) ◽  
pp. 4-8
Author(s):  
M.N. Tillyashajhov ◽  
S.V. Kamyshov ◽  
E.V. Bojko
Keyword(s):  
Overall Survival ◽  
Control Point ◽  
Surface Protein ◽  
New Drugs ◽  
Phase Iii ◽  
Second Line ◽  
First Line ◽  
Critical Question ◽  
Accelerated Approval ◽  
New Biomarkers

For a long time, chemotherapy remained the main treatment option for metastatic urothelial carcinoma (mUC). Over the past year, there have been revolutionary changes associated with the approval of five new drugs aimed at blocking the interaction between the surface protein of T‑lymphocytes PD‑1 and its ligands PD‑L1 and PD‑L2, resulting in the activation of the immune response. It is noteworthy that the anti‑PD‑1 antibody pembrolizumab demonstrated an increase in overall survival relative to chemotherapy in a randomized phase III trial in the second line with mUC. Based on this level 1 evidence pembrolizumab was approved by the US Food and Drug Administration (FDA). Nivolumab (antibody PD‑1) also demonstrated an increase in overall survival compared to historical control and was approved by FDA. Likewise, antibodies targeting PD‑L1, including atezolizumab, durvalumab and avelumab, received accelerated approval from the FDA as the second line of treatment for mUC. Some of these agents are approved in the first line by the results of phase II study (atezolizumab and pembolizumab received accelerated approval for first‑line treatment in patients not receiving cisplatin). Despite these many endorsements, clinical development of new biomarkers for selection of patients, who can get maximum advantages of immunotherapy and also for development the optimal therapy sequencing still are biggest and critical question for future investigation.The clinical introduction of biomarkers to determine optimal treatment of patients remains extremely important.

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