Combination Of Platinum Compounds Research Articles

Abstract 5270: HSP90 identified by a proteomic approach as druggable target to reverse platinum-resistance in ovarian cancer

Abstract INTRODUCTION: Epithelial ovarian cancer (EOC) represents the gynecologic cancer with the highest mortality rate. Despite a high initial response to platinum (PT)-based chemotherapy, the majority of patients with advanced EOC relapses and develops chemo-resistance that results in treatment failure and poor prognosis. Therefore, understanding the mechanisms underlying PT-resistance and finding strategies to overcome them are urgently needed. METHODS: Three isogenic models of PT-resistance generated by our group from EOC cell lines (TOV-112D, OVSAHO and MDAH) (Sonego M. et al, 2017), were characterized by a proteomic approach taking advantage of two-dimensional differential in gel electrophoresis (2-D DIGE) followed by Mass Spectrometry. Proteomics data were also analyzed by the ingenuity pathway analysis (IPA) software. Synergistic anti-proliferative activity was evaluated by calculating combination indexes (CI) by the Chou-Talalay method and colony formation assay. Apoptosis was measured by flow-cytometry and by western blotting evaluation of caspase-3 and PARP cleavage. In vivo experiments were performed on xenograft model in athymic mice. RESULTS: We identified 23, 24 and 20 differentially expressed proteins in PT-resistant TOV-112D, OVSAHO and MDAH respectively, compared with parental cells. A relevant relationship between all the identified proteins in the three models was highlighted by IPA. Interestingly, eight of the identified proteins, HSP7C, HNRPL, ATPA, EFTU, PHB, HNRPK, LMNA and PHGDH, shared at least within two cell lines, are all included in one main network related with cancer. Notably, the protein chaperone HSP90 emerged as a central hub of this network and its up-regulation was observed in all the PT-resistant cell lines compared with parental counterparts. Further molecular characterization also showed overexpression of HSF1 transcription factor, a relevant HSP90 activator and client protein, in PT-resistant cells. On this bases, we evaluated the effect of cisplatin in combination with two HSP90 inhibitors (17AAG or ganetespib), both in phase II/III clinical development in cancer patients, observing synergistic anti-proliferative activity and reduced colony formation, particularly in PT-resistant cells. These data were confirmed in primary cultures from PT-Resistant ovarian cancer patients. Furthermore we confirmed for the first time in vivo the synergistic antitumor effect of cisplatin and ganetespib combination in TOV112D PT-resistant xenograft model. Increased pro-apoptotic effect and DNA-damage induction by the combination treatment compared to untreated or single agents treated tumors was confirmed both in vitro and in vivo. CONCLUSIONS: Our data suggest an innovative antitumor strategy based on the combination of platinum compounds with HSP90 inhibitors, to re-challenge PT-resistant EOC, that warrants further clinical evaluation. Citation Format: Rita Lombardi, Maura Sonego, Laura Addi, Federica Iannelli, Francesca Capone, Maria Serena Roca, Maria Rita Milone, Alice Costa, Francesca Bruzzese, Biagio Pucci, Gustavo Baldassarre, Alfredo Budillon. HSP90 identified by a proteomic approach as druggable target to reverse platinum-resistance in ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5270.

Abstract OT1-03-10: A phase I followed by a randomized phase II trial of two cycles carboplatin-olaparib followed by olaparib monotherapy versus capecitabine in BRCA-1 or -2 mutated Her2 negative advanced breast cancer as first line treatment (REVIVAL study)

Abstract Background Preclinical studies revealed that the combination of platinum compounds and olaparib is additive and possibly even synergistic in cell models with BRCA1 or -2 mutations. Early clinical trials suggested high benefit of olaparib with induction carboplatin in BRCA1 and -2 mutation carrier enriched populations. However, there is no evidence yet that carboplatin-olaparib has a superior benefit-risk compared to current standard therapy in advanced breast cancer in BRCA1 and -2 mutation carriers. Trial design We initiated a phase-I/II study due to an olaparib formulation change from capsule to tablet. During phase-I a traditional 3+3 dose escalation study is performed. Carboplatin will be dose escalated in 1 step from AUC 3 to AUC 4 with a constant olaparib dose of 25 mg BID. Olaparib is then dose escalated in 3 steps to 50, 75 and 100 mg BID until > 1/6 patients develop a DLT, the previous safe dose-level will be determined the MTD. After the MTD is established a randomised phase-II trial will be initiated where patients are randomised between standard capecitabine 1250 mg/m2 BID day 1-14, q day 22 or 2 cycles carboplatin-olaparib followed by olaparib monotherapy 300mg BID. After progression, patients in the experimental arm receive capecitabine, all other patients receive physicians choice of paclitaxel, vinorelbine or eribulin at standard dose. A compassionate use program with olaparib is available for patients in the standard arm after progression on second line treatment. Eligibility criteria In phase-II patients with histological or cytological proof of advanced BRCA1 or -2 mutated HER2 negative breast cancer are eligible if they are ≥18 years, have measureable disease according to RECIST 1.1 criteria, a WHO performance status of 0–2, a life expectancy ≥ 3 months and a negative pregnancy test. Pretreatment should contain an anthracycline and/or taxane in the (neo)adjuvant setting, unless not indicated. In the advanced setting only hormonal pre-treatment is allowed. Minimal laboratory values ANC ≥ 1.5 x 109 /L, Hb ≥ 6.2 mM (no transfusions in the last 28 days), platelet count ≥ 100 x 109 /L, serum bilirubin < 1.5 x ULN, ASAT and ALAT < 2.5 x ULN and a serum creatinine < 1.5 x ULN or creatinine clearance ≥ 50 mL/min. Aims In phase-1 we establish the MTD for treatment in phase-II where we study progression free survival on first line treatment(PFS1) compared with standard of care capecitabine. Statistical methods Toxicity analysis in phase-I can take place after all patients completed their 28 day DLT period. A total of 104 events in 110 patients on first line treatment need to be observed in phase-II to detect a clinical meaningful improvement in median PFS1 in the experimental arm from 4 to 7 months, assuming an accrual of 2 years and a follow-up of ≥6 months, providing a power of 80% (two-sided significance level of 5%). An interim analysis for futility and efficacy will be performed when 52 events have been observed. Accrual It is expected that 15-20 patients are needed in phase-I, inclusion is due around November 2015. Phase-II will be multicentre and is expected to start accrual December 2015. Citation Format: Dackus GMHE, Schouten PC, Geenen JJ, Marchetti S, Sonke GS, Linn SC, Schellens JHM. A phase I followed by a randomized phase II trial of two cycles carboplatin-olaparib followed by olaparib monotherapy versus capecitabine in BRCA-1 or -2 mutated Her2 negative advanced breast cancer as first line treatment (REVIVAL study). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-10.

Neuroendocrine Carcinoma of the Breast: Current Evidence and Future Perspectives.

: Neuroendocrine carcinoma of the breast is considered a rare entity, and for this reason there are no data from prospective clinical trials on its optimal management. Early stage tumors are usually treated with the same strategy used for the other types of invasive breast cancer. Anthracycline- and taxane-based regimens represent the most frequently administered chemotherapy in neoadjuvant and adjuvant setting, as well as for metastatic disease, although combinations of platinum compounds and etoposide have been widely used, in particular for small-cell histology and tumors with a high proliferation index. For metastatic disease, a multimodality therapeutic strategy can be considered on an individual basis, with chemotherapy, endocrine therapy, peptide receptor radionuclide therapy, radiation therapy, surgery, or a combination of the above. In the near future, a better knowledge of the biology of these tumors will hopefully provide new therapeutic targets for personalized treatment. In this review, we discuss the current evidence and the future perspectives on diagnosis and treatment of neuroendocrine carcinoma of the breast. Neuroendocrine carcinoma of the breast (NECB) is a distinct entity of breast cancer. Clinical features and morphology are not helpful to distinguish NECB from other subtypes of breast cancer; therefore, immunohistochemistry markers for neuroendocrine differentiation, mainly chromogranin and synaptophysin, should be routinely used to confirm the diagnosis, especially in cases of mucinous or solid papillary carcinoma in which the suspicion of NECB may be relevant. Adjuvant treatment should be offered according to the same recommendations given for the other types of invasive breast cancer. An accurate diagnosis of NECB is also important in the metastatic setting, in which a multimodality approach including specific therapies such as peptide receptor radionuclide therapy can be considered.

Abstract 2534: Sequenced combinations of platinum drugs and phytochemicals towards overcoming drug resistance in ovarian cancer

Abstract Background and aims Resistance to platinum-based chemotherapy remains a major obstacle in the treatment against human ovarian cancer. In this study, binary combinations of platinum compounds: cisplatin, carboplatin and oxaliplatin with phytochemicals: artemisinin, thymoquinone, curcumin, lupeol and oleanolic acid have been applied to human ovarian cancer cell lines: A2780, A2780cisR, and A2780ZD0473R using three different sequences of administration (0/0h, 0/4h and 4/0h) where 0/0h means both the drugs added at the same time, 0/4h means platinum added first followed phytochemical 4 h later and 4/0h means the converse. Methods Cytotoxicity was determined based on MTT reduction MTT assay. Median effect analysis was done to characterize combined drug action and combination Index (CI) was used as a measure of synergism or antagonism whereas cellular accumulation of platinum, platinum to DNA binding levels and proteomic studies were done to provide insight into drug resistance and synergism from combined drug action. Results The combinations of platinum and the phytochemicals produced sequence- and concentration-dependent synergism in the ovarian tumour models. The degree of synergism was greater in the resistant cell lines than the parent cell line. It was found that combination with phytochemicals also increased intracellular accumulation of platinum and the level of platinum binding with DNA. Proteomic study identified a number of proteins believed to be associated with cisplatin resistance in ovarian cancer cells A2780 and A2780cisR. The expression of the proteins were either down- or up-regulated in A2780cisR cell line as compared to A2780 cell line but fully or partially restored after treatment with synergistic combinations. Conclusion The results of the study indicate that appropriately sequenced combinations of platinum drugs and phytochemicals can provide a means of overcoming drug resistance in ovarian cancer. Citation Format: Safiah I. Althurwi, Jun Qing Yu,, Philip Beale, Charles Chan, Fazlul Huq. Sequenced combinations of platinum drugs and phytochemicals towards overcoming drug resistance in ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2534. doi:10.1158/1538-7445.AM2015-2534

Predictive value of STMN1 gene promoter polymorphism (-2166T>C) in patients with advanced NSCLC treated with the combination of platinum compounds and vinorelbine.

PurposeThe combination of platinum compounds and vinorelbine is often used as a first-line treatment in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC), without activating EGFR mutations and ALK rearrangement. Unfortunately, less than half of the patients benefit from chemotherapy. Moreover, majority of patients are exposed to a number of side effects of chemotherapy. Stathmin-1 (STMN1, oncoprotein 18) affects significantly microtubule dynamics and formation of the mitotic spindle. Therefore, the change in the STMN1 gene may be a potential predictive factor of response to treatment regimens containing a cytostatics-disrupting microtubule dynamics (vinca alkaloids and taxoids). The aim of the study was to determine the relationship between a single nucleotide polymorphism (SNP) of the promoter of STMN1 gene −2166T>C) and the effectiveness of chemotherapy based on platinum compounds and vinorelbine in patients with NSCLC.MethodsThe investigated population consisted of 110 locally advanced or metastatic NSCLC patients treated with first-line chemotherapy, based on platinum compounds and vinorelbine. SNP was determined by SNaPshot™ PCR in DNA isolated from peripheral blood leukocytes.ResultsThe median progression-free survival (PFS) was significantly shorter in carriers of TT genotype of the STMN1 gene compared with patients with CC or CT genotypes (2.75 vs. 6.5 months; p = 0.0033; HR 5.91, 95 % CI 1.81–19.33). Evaluated SNP did not significantly affect the response to treatment and the overall survival of the patients.ConclusionRare TT genotype of STMN1 gene may be an unfavorable predictive factor of chemotherapy based on platinum compounds and vinorelbine, in patients with NSCLC.

ERCC1 and Thymidylate Synthase as Prognostic Biomarkers in Malignant Mesothelioma

The standard of care for malignant pleural mesothelioma (MPM) is a combination of platinum compounds and Pemetrexed. Still, the median survival of MPM patients is low (about 12 months). Excision Repair Cross Complementing Group 1 (ERCC1) acts by removing DNA adducts formed by platinum compounds, whereas Pemetrexed inhibits Thymidylate Synthase (TS), which is involved in DNA synthesis.Pleural biopsies were collected from 140 MPM patients (98 males and 42 females, mean age 68 years) before treatment initiation. Average disease specific survival was 13 months (range 1‐60). mRNA was extracted from formalin fixed paraffin blocks, reverse transcribed and assayed by qRT‐PCR. Immunohistochemistry with anti‐ERCC1 and anti‐TS mAbs was scored semi‐quantitatively.Of 140 patients, 102 were treated, the remaining were not because of bad performance status or advanced age. Patients with low ERCC1 protein expression survived longer (24.3 vs 12.5 months, P=.03). Likewise, patients with low levels of TS mRNA had better survival (P=.01); there was no advantage, however, in the treated sub‐group, suggesting that Pemetrexed treatment and low TS expression had no additive value.ERCC1 protein expression and TS gene expression both seem important prognostic markers; we suggest their evaluation in routine biopsies from MPM patients.

Neoadjuvant, Anthracycline-Free Chemotherapy with Carboplatin and Docetaxel in Triple-Negative, Early-Stage Breast Cancer: A Multicentric Analysis of Feasibility and Rates of Pathologic Complete Response

Background: Triple-negative breast cancer (TNBC) attracts a disproportionate share of intensive research because of its poor prognosis. Standard anthracycline- and taxane-based regimens still yield an unsatisfactorily low rate of pathologic complete response (pCR). The pCR rate is a recognized surrogate marker for good long-term survival. Methods: A multicentric, retrospective study was conducted including all patients not willing to undergo or not suitable for an anthracycline-based regimen. Six cycles of docetaxel 75 mg/m² and carboplatin AUC 6 q3w were administered. The primary endpoint was pCR (ypT0/ypTis + ypN0) and near-pCR (≤5 mm residual disease). The secondary endpoint was feasibility (CTCAE version 4.03 criteria) and adherence to treatment. Results: Six cycles of carboplatin AUC 6 and docetaxel 75 mg/m² resulted in a high pCR rate of 50% and a combined pCR/near-pCR rate of 70%. Grade 3 and 4 toxicities were rare events and 28 of 30 (93%) patients completed all 6 cycles. No toxicity-related treatment discontinuation and no febrile neutropenia were registered. Conclusion: This chemotherapy regimen provides a highly effective and feasible strategy for patients not willing to receive or not suitable for an anthracycline-based treatment (cardiac ejection fraction <65% or age >65 years). Combinations of platinum compounds with taxanes and anthracyclines may be also desirable in TNBC.

Improving the accuracy of FNA lung biopsies in a community hospital.

7639 Background: Until 2008 it was believed that outcomes in NSCLC were independent of histologic type. Until then, all doublet combinations of platinum compounds showed comparable efficacy in the ...

Capecitabine in advanced gastric cancer

Since the routine introduction of chemotherapy for advanced gastric cancer in the early 1990s, median survival for gastric cancer has improved from 3 months, with best supportive care alone, to > 11 months in recently reported Phase III trials of triplet chemotherapy. Capecitabine is an orally-active fluoropyrimidine, which is selectively metabolised to fluorouracil in tumour cells. The combinations of platinum compounds and capecitabine have been evaluated in two recent, large, Phase III trials demonstrating non-inferiority in efficacy compared with platinum plus continuous infusion fluorouracil. In view of the convenience and flexibility of patients in adjusting dosage when encountering toxicities, capecitabine is replacing continuous infusion fluorouracil as the backbone of combination chemotherapy in advanced gastric cancer patients. Future trials evaluating biologicals are now incorporating capecitabine combinations as control arms in both advanced disease and peri-operative settings in gastric cancer.