作者: Sheikh, Nadeem ; Karzai, Fatima ; Gulley, James L. ; Fakhrejahani, Farhad ; Vu, Tuyen ; Cordes, Lisa ; Madan, Ravi A. ; Schlom, Jeffrey ; Redman, Jason M. ; Dahut, William L.

Therapeutic cancer vaccines including sipuleucel-T, a prostatic acid phosphatase (PAP) targeted vaccine that improves survival in metastatic castration-resistant prostate cancer (mCRPC), can produce immune responses that translate to clinical benefit. The effects of sequential checkpoint inhibitors after therapeutic vaccine on immune responses are unknown. Avelumab is an anti–programmed death ligand-1 monoclonal antibody evaluated in patients with mCRPC in the JAVELIN solid tumor phase 1 trial expansion cohort, enriched for patients with a previous therapeutic prostate cancer-targeted vaccine. mCRPC patients received intravenous avelumab 10 mg/kg every 2 weeks with imaging every 6 weeks. Peripheral blood T-cell responses to PAP and to PA2024, the peptide containing PAP utilized by the vaccine, were evaluated pre and posttreatment. Eighteen patients enrolled, and previous treatments included abiraterone or enzalutamide in 14 (78%), therapeutic cancer vaccine in 14 (78%), and chemotherapy in 4 (22%). Avelumab had a manageable safety profile. There were no sustained prostate specific antigen decreases. Of 17 patients evaluable for best overall response by RECISTv1.1, 12 had stable disease (SD) and 5 had progressive disease. Seven patients had SD for >24 weeks posttreatment. Fourteen patients had previously received therapeutic cancer vaccines. Eleven (79%) had SD as the best overall response. Of these 14 patients, 9 had previously received sipuleucelT. Analysis of antigen-specific T-cell responses pre and postavelumab treatment did not demonstrate changes in interferon-γ production or proliferation in response to PAP or PA2024. This unplanned analysis does not support the use of sequential therapeutic cancer vaccine therapy followed by programmed death ligand-1 inhibition in mCRPC.

2021-12-09·Anti-Cancer Agents in Medicinal Chemistry4区 · 医学

Multi-Component Reactions of Cyclohexan-1,3-dione: Synthesis of Fused Pyran, Pyridine, Thiophene and Pyrazole Derivatives with c-Met, Anti-Proliferative Activities

4区 · 医学

Article

作者: Mohareb, Rafat M. ; Elmetwally, Amira M. ; Mohamed, Abeer A.

Background:Recently, products of Multi-Component Reactions (MCR’s) acquired special attention due to their wide range of pharmacological activities especially therapeutic activities. In the market it was found that many pharmacological drugs containing the pyran and pyridine nucleus that were produced through MCR’s were found.Objective:This work aims to synthesize target molecules not only possess anti-tumour activities but also c-Met and prostate cancer inhibitors. The target molecules were obtained starting from cyclohexan-1,3-dione through its multi-component reactions to produce anticancer target molecules.Methods:Cyclohexane-1,3-dione underwent different multi-component reactions to produce fused pyran, pyridine and thiophene derivatives. The anti-proliferative activity of the newly synthesized compounds among the synthesized compounds toward the six cancer cell lines, namely A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721 was studied. In addition, inhibitions toward c-Met kinase and prostate cancer cell line were studied. Antitumor evaluations toward seventeen cancer cell lines subpanel, for certain compounds, were also demonstrated according to the diseases. Pim-1 kinase inhibitions of the most active compounds were also measured.Results:Anti-proliferative evaluations, c-Met and Pim-1 kinase inhibitions were performed for most of the synthesized compounds where the varieties of substituent through the aryl ring and the heterocyclic ring afforded compounds with high activities.Conclusion:Compounds 4b, 6b, 8b, 9a, 11b, 12b, 17b, 18b, 19, 22c, 23b, 25b and 26b were the most cytotoxic compounds toward the six cancer cell lines. Inhibitions toward c-Met kinase and prostate cancer cells showed that the presence of the electronegative Cl group within the molecule were responsible for its high activity. In addition, inhibitions toward Pim-1 kinase exhibited that most of tested compounds showed high inhibitions.

2021-03-01·Journal of Medical Imaging and Radiation Sciences

Prostate or bone? Comparing the efficacy of image guidance surrogates for pelvis and prostate radiotherapy using accumulated delivered dose

Article

作者: Catton, Charles ; Kong, Vickie C ; Chung, Peter ; Bayley, Andrew ; Warde, Padraig ; Rosewall, Tara ; Craig, Tim

INTRODUCTIONThis study assessed the impact of dosimetry to both the target and normal tissue when either bony anatomy (BA) or prostate (PRO) was used as surrogates for image guidance for pelvis and prostate radiotherapy using a dose accumulation process.METHODSThirty patients who were prescribed 50-54Gy to the pelvic lymph nodes (PLN) and 78Gy to the prostate/seminal vesicles were included. Daily acquired CBCTs were rigidly registered to the CT using BA and PRO to simulate two different treatment positions. The accumulated delivered dose (D_Acc) of PLN, prostate, bladder and rectum for each surrogate were compared with the planned dose. Deviation from the planned dose (ΔD_Acc-Plan) of >5% was considered clinically significant.RESULTSProstate was displaced from bony anatomy by > 5 mm in 96/755 fractions (12.7%). Deviation between the mean D_Acc and the planned dose for PLN and prostate was <2% when either BA or PRO was used. No significant deviation from planned dose was observed for bladder (p > 0.2). In contrary, D_Acc for rectum D₅₀ was significantly greater than the planned dose when BA was used (Mean ΔD_Acc-Plan = 6%). When examining individual patient, deviation from the planned dose for rectum D₅₀ was clinically significant for 18 patients for BA (Range: 5-21%) and only 8 patients for PRO (Range: 5-8%).CONCLUSIONSThe use of either BA or PRO for image guidance could deliver dose to PLN and prostate with minimal deviation from the plan using existing PTV margins. However, deviation for rectum was greater when BA was used.

100 项与 Prostate cancer(OncoTartis) 相关的药物交易

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