Publications by authors named "Michele Caruso"

38 Publications

Reactions and countermeasures of medical oncologists towards the incoming COVID-19 pandemic: a WhatsApp messenger-based report from the Italian College of Chief Medical Oncologists.

Ecancermedicalscience 2020 15;14:1046. Epub 2020 May 15.

Medical Oncology Unit, Ospedale La Maddalena, University of Palermo, Palermo, 90100, Italy.

Background: This descriptive, unplanned investigation has been undertaken to report reactions, attitudes and countermeasures which have been put in place and implemented by medical oncology units facing the COVID-19 outbreak in Southern Italy.

Materials And Methods: Data have been retrospectively obtained from the time-related analysis of conversations via a WhatsApp messenger-based group chat between the medical directors belonging to the Italian College of Medical Oncology Directors. Overall number, intensity and time trend of conversations related to reactions during the 4 weeks of observation related to the crucial events which occurred between 24 February and 28 March, 2020 2020 are included. A sentiment analysis of conversations was also carried out.

Results: We report 956 conversations among 19 medical oncology units related to reactions to the crucial events, such as epidemic spread, Government ordinances and guidelines during the 4 weeks of observation. Data show significant awareness of problems linked to the COVID-19 spread among oncologists and rapid diffusion of countermeasures. Actions taken were correlated time wise to crucial events. A correlation between conversations and the volume of activity of oncology units was found. By analysing the sentiment analysis of raw data, positive emotions were reduced in percentage over the weeks. A significant increase in negative emotions was observed as the outbreak impacted on the healthcare system.

Conclusion: In our experience, the WhatsApp instant-messaging system seems to be a useful tool to share news and reactions between medical oncologists to rapidly implement necessary health measures and answers to most cancer patients' needs and queries in the COVID-19 pandemic scenario.
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http://dx.doi.org/10.3332/ecancer.2020.1046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289620PMC
May 2020

Eribulin mesylate use as third-line therapy in patients with metastatic breast cancer (VESPRY): a prospective, multicentre, observational study.

Ther Adv Med Oncol 2019 19;11:1758835919895755. Epub 2019 Dec 19.

Humanitas Centro Catanese di Oncologia, Catania, Italy.

Background: In real-world practice, eribulin mesylate provides significant survival benefit, with a manageable safety profile in heavily pretreated patients with metastatic breast cancer (MBC).

Methods: In this prospective, open-label, multicentre, observational study we evaluated the effectiveness and tolerability of eribulin as third-line treatment in a homogeneous population. The primary endpoints were the safety profile and response in metastatic sites; secondary endpoints included the response in different subtypes, overall response rate (ORR), progression-free survival (PFS) and overall survival (OS).

Results: From 2013 to 2016, 118 women were treated in 21 Sicilian institutions; the median age was 58 years (range 29-79), with 69% of patients under 65. The median cycles of eribulin were 5.5 (range 1-26). The most common adverse event was neutropenia (9.3%, 3 cases of grade 3, 4 of grade 4); only 1 case of QT prolongation was reported. Eribulin was effective in controlling metastatic disease in all sites, and it achieved the highest ORR in brain (16%) and liver (14.9%). Median OS was 31.8 months (95% CI 27.9-34.4) and median PFS 5.5 months (95% CI 4.2-6.6). PFS was 5.2 months (95% CI 2.8-8.4) in patients with triple-negative subtype. Median PFS was longer in patients over 65 years (6.1 months, 95% CI 4.4-8.3). In patients who had visceral metastases PFS was 5.5 months (95% CI 95% 3.5-6.6) and OS 33.9 months (95% CI 29.8-40.8).

Conclusions: Eribulin as third-line treatment shows an acceptable safety profile and a substantial antitumour activity in the treatment of MBC, even in elderly patients and in those with visceral disease.
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http://dx.doi.org/10.1177/1758835919895755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923689PMC
December 2019

The impact of cancer: An Italian descriptive study involving 500 long-term cancer survivors.

Eur J Cancer Care (Engl) 2019 May 10;28(3):e13007. Epub 2019 Feb 10.

Unit of Oncological Psychology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.

Introduction: The well-being and quality of life (QoL) of long-term cancer survivors may be affected, both positively and negatively, by psychosocial factors related to the experience of being a cancer patient. We investigated whether, in long-term cancer survivors, the psychosocial impacts of cancer associate with socio-demographic-clinical variables; whether, within the positive and negative dimensions taken separately, some impacts are more intense than others; and whether these impacts explain QoL.

Methods: Italian long-term cancer survivors (n = 500) completed the Impact of Cancer (IOC-V2) and Short Form 36 Health Survey (SF-36) questionnaires.

Results: The IOC-V2 negative impact score associated with gender, education, occupational status and health issues, whereas no association was found between the positive impact score and socio-demographic-clinical variables. Of the positive impacts, Altruism/Empathy was the highest (p < 0.001); Positive self-evaluation was higher than Health awareness (p = 0.001); and Meaning of cancer was the lowest (p < 0.001). Among the negative impacts, Worry was the highest (p < 0.001), whereas Body changes concerns was higher than both Appearance concerns (p < 0.001) and Life Interferences (p < 0.001). The assessed impacts explained more than 25% of the variance of both physical and mental functioning scores.

Conclusions: The provided data document psychosocial factors affecting QoL in Italian long-term cancer survivors.
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http://dx.doi.org/10.1111/ecc.13007DOI Listing
May 2019

Neutrophil Elastase Promotes Linker Cleavage and Paclitaxel Release from an Integrin-Targeted Conjugate.

Chemistry 2019 Feb 27;25(7):1696-1700. Epub 2018 Dec 27.

Università degli Studi di Milano, Dipartimento di Chimica, Via C. Golgi, 19, I-20133, Milan, Italy.

This work takes advantage of one of the hallmarks of cancer, that is, the presence of tumor infiltrating cells of the immune system and leukocyte-secreted enzymes, to promote the activation of an anticancer drug at the tumor site. The peptidomimetic integrin ligand cyclo(DKP-RGD) was found to accumulate on the surface of α β integrin-expressing human renal cell carcinoma 786-O cells. The ligand was conjugated to the anticancer drug paclitaxel through a Asn-Pro-Val (NPV) tripeptide linker, which is a substrate of neutrophil-secreted elastase. In vitro linker cleavage assays and cell antiproliferative experiments demonstrate the efficacy of this tumor-targeting conjugate, opening the way to potential therapeutic applications.
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http://dx.doi.org/10.1002/chem.201805447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471013PMC
February 2019

T-DM1 and brain metastases: Clinical outcome in HER2-positive metastatic breast cancer.

Breast 2018 Oct 12;41:137-143. Epub 2018 Jul 12.

Oncologia Medica 1, Istituto Nazionale Tumori "Regina Elena", Roma, Italy.

Background: We reported the results of an Italian large retrospective analysis that evaluated the effectiveness and safety of T-DM1 in 'field-practice' breast cancer patients. We performed a sub-analysis to investigate the clinical activity of T-DM1 in patients with brain metastases (BMs).

Methods: The records of 87 adult women with HER2-positive breast cancer and BMs treated with T-DM1 were reviewed. Their clinical outcomes were compared with those of 216 patients without central nervous system (CNS) involvement.

Results: Response to T-DM1 treatment in BMs was available for 53 patients in the BM group (60.9%): two patients reported a complete response (3.8%), 11 patients obtained partial response (20.7%; overall response rate: 24.5%), 16 patients had a stable disease (30.1%). Regarding extracranial disease, a total of 77 and 191 patients were evaluable for response in BM group and non-BM group, respectively. The overall response rate was 35.1% in the BM group and 38.3% in the non-BM group; disease control rate was 53.3% and 66.6%, respectively. At a median follow-up of 16 months (range: 1-55), median cumulative progression-free survival (PFS) was 7 months (95% CI: 5.4-8.6) in the BM group and 8 months (95% CI: 5.7-10.3) in the non-BM group. In the second-line setting, PFS was 5 (95% CI: 3.1-6.9) versus 11 (95% CI: 7.1-14.9) months (p = 0.01). Overall survival was 14 months (95% CI: 12.2-15.8) in the BM group and 32 months (95% CI: 24.4-39.6) in the non-BM group (p < 0.0001).

Conclusions: T-DM1 is active in breast cancer patients with BMs.
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http://dx.doi.org/10.1016/j.breast.2018.07.004DOI Listing
October 2018

Phase II Study of Everolimus in Patients With Thymoma and Thymic Carcinoma Previously Treated With Cisplatin-Based Chemotherapy.

J Clin Oncol 2018 02 14;36(4):342-349. Epub 2017 Dec 14.

Paolo Andrea Zucali, Matteo Simonelli, Matteo Perrino, Fabio De Vincenzo, Laura Giordano, Monica Bertossi, Annarita Destro, Luca Di Tommaso, and Armando Santoro¸ Humanitas Clinical and Research Hospital; Tommaso De Pas, Francesca Toffalorio, Fabio Conforti, and Angela Cioffi, European Institute of Oncology; Paolo Andrea Zucali, Matteo Simonelli, Luca Di Tommaso, and Armando Santoro, Humanitas University, Milan; Giovannella Palmieri, Vincenzo Damiano, Margaret Ottaviano, and Sabino De Placido, Università Federico II, Naples; Adolfo Favaretto and Giulia Pasello, Istituto Oncologico Veneto, Padua; Antonio Chella and Erika Garbella, University Hospital, Pisa; Marcello Tiseo, Azienda Ospedaliero-Universitaria of Parma, Parma; and Michele Caruso and Marco Ali, Humanitas Centro Catanese di Oncologia, Catania, Italy.

Purpose No effective salvage treatments are available for patients with advanced/recurrent thymoma (T) or thymic carcinoma (TC) who have progressed after platinum-based chemotherapy. This study evaluated the activity of everolimus in patients with advanced/recurrent T or TC previously treated with cisplatin-containing chemotherapy. Patients and Methods This was a single-arm, single-stage, open-label, multicenter, phase II trial. Patients received oral everolimus 10 mg/d until disease progression, unacceptable toxicity, or patient refusal. A Fleming phase II trial was designed. The null hypothesis of a true disease control rate (DCR) of 40% was tested against a one-sided alternative of a true DCR of 60% (α = β = 0.10): If disease control were achieved in ≥ 21 of the first 41 evaluable patients, everolimus could be recommended for further evaluation. Progression-free survival, overall survival, and safety were also evaluated. Results From 2011 to 2013, 51 patients were enrolled (T, n = 32; TC, n = 19). Complete remission was observed in one patient with TC, partial response in five patients (T, n = 3; TC, n = 2), and stable disease in 38 patients (T, n = 27; TC, n= 11), with a DCR of 88% (T,: 93.8%; TC, 77.8%). With a median follow up of 25.7 months, median progression-free survival was 10.1 months (T,: 16.6 months; TC, 5.6 months), and median overall survival was 25.7 months (T, not reached; TC, 14.7 months). Fourteen patients had a serious drug-related adverse event; of these patients, nine permanently discontinued treatment. Three patients died of pneumonitis while in the study. Immunohistochemical positivity for p4E-BP1 or insulin-like growth factor-1 receptor was statistically significantly related to a shorter survival. Conclusion Everolimus may induce durable disease control in a high percentage of patients with T or TC, albeit with a potential high risk of fatal pneumonitis.
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http://dx.doi.org/10.1200/JCO.2017.74.4078DOI Listing
February 2018

Ado-trastuzumab emtansine (T-DM1) in HER2+ advanced breast cancer patients: does pretreatment with pertuzumab matter?

Future Oncol 2017 Dec 28;13(30):2791-2797. Epub 2017 Nov 28.

Oncologia Medica 1, Istituto Nazionale Tumori 'Regina Elena', Roma, 00144, Italy.

Aim: We evaluated the outcomes of patients treated with ado-trastuzumab emantasine (T-DM1) after first-line pertuzumab/trastuzumab, compared with those receiving a trastuzumab-only-based regimen.

Patients & Methods: Patients who received second-line T-DM1 after pertuzumab/trastuzumab (n = 34) were compared with those who received only trastuzumab (n = 73).

Results: Overall response rate was 33.3% in patients with prior pertuzumab and 57.1% in the remaining subjects. Disease control rate was 47 and 43%, respectively, and the clinical benefit rate was 43.3 and 71.1%, respectively. Median progression-free survival was 5.0 and 11.0 months, respectively (hazard ratio: 2.02; 95% CI: 1.14-3.58; p = 0.01).

Conclusion: Patients treated with T-DM1 who previously received pertuzumab present poorer clinical outcomes compared with those receiving a trastuzumab-only-based regimen in the first-line setting.
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http://dx.doi.org/10.2217/fon-2017-0336DOI Listing
December 2017

The prognostic significance of combined androgen receptor, E-Cadherin, Ki67 and CK5/6 expression in patients with triple negative breast cancer.

Oncotarget 2017 09 16;8(44):76974-76986. Epub 2017 Aug 16.

Medical Oncology Unit A.O. Papardo & Department of Human Pathology University of Messina, Messina, Italy.

Background: Triple Negative Breast Cancer (TNBC) represents a heterogeneous group of tumors with poor prognosis owing to aggressive tumor biology and lack of targeted therapies. No clear prognostic biomarkers have been identified to date for this subgroup.

Materials And Methods: In this retrospective study we evaluated the prognostic role of 4 different molecular determinants, including androgen receptor (AR), E-cadherin (CDH1), Ki67 index, and basal cytokeratins (CKs) 5/6, in a cohort of 99 patients with TNBC. All patients received neo/adjuvant chemotherapy (mostly anthracycline/taxane-based). Immunohistochemistry (IHC) was performed in formalin-fixed paraffin-embedded primary tumor samples. CDH1 expression was considered positive as ≥ 30% of the membrane cells staining. AR positivity was defined as > 10% of positive tumor cells. High Ki67 was defined as ≥20% positive tumor cells. CK5/6 expression was judged positive if the score was ≥1.

Results: The absence of AR expression was significantly associated with highly undifferentiated tumors. Univariate analyses showed that lack of expression of CDH1, tumor size and nodal status were significantly correlated with worse RFS and OS (p< 0.05). AR expression and low Ki67 showed a trend towards better RFS and OS. Patients with absent CK5/6 expression in univariate and multivariate analyses had poorer RFS (p=0.02 and p=0.002, respectively) and OS (p=0.05 and p=0.02, respectively). Multivariate analysis showed an independent association between CDH1 expression and better RFS and OS (p< 0.05) beyond tumor size, nodal status, and grade. The Kaplan-Meier curves showed that patients with AR and CDH1 negative expression and high Ki-67 levels have a significant correlation with poor outcome.

Conclusions: Our study supports the use of IHC expression of AR, CDH1, Ki67, and CK5/6 as prognostic markers in TNBCs and suggests a link between their expression and prognosis and may help to stratify TNBC patients in different prognostic classes.
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http://dx.doi.org/10.18632/oncotarget.20293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652756PMC
September 2017

Efficacy and safety of T-DM1 in the 'common-practice' of HER2+ advanced breast cancer setting: a multicenter study.

Oncotarget 2017 09 18;8(38):64481-64489. Epub 2017 Mar 18.

Oncologia Medica 1, Istituto Nazionale Tumori "Regina Elena", Roma, Italy.

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate approved for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive, metastatic breast cancer (mBC). The aim of this 'field-practice' study was to investigate the efficacy and safety of T-DM1, focusing on treatment line, previous lapatinib treatment and patterns of metastasis. Three hundred and three patients with HER2-positive mBC who received T-DM1 were identified by reviewing the medical records of 24 Italian Institutions. One hundred fourty-nine (49%) and 264 (87%) had received prior hormonal treatment and/or anti-HER2 targeted therapy, respectively. Particularly, 149 patients had been previously treated with lapatinib. The objective response rate (ORR) was 36.2%, and 44.5% when T-DM1 was administrated as second-line therapy. Considering only patients with liver metastases, the ORR was 44.4%. The median progression-free survival (PFS) was 7.0 months in the overall population, but it reached 9.0 and 12.0 months when TDM-1 was administered as second- and third-line treatment, respectively. In conclusion, in this 'real-word' study evaluating the effects of T-DM1 in patients with HER2-positive mBC who progressed on prior anti-HER2 therapies, we observed a clinically-relevant benefit in those who had received T-DM1 in early metastatic treatment-line and in subjects previously treated with lapatinib.
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http://dx.doi.org/10.18632/oncotarget.16373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610019PMC
September 2017

Long-term quality of life profile in oncology: a comparison between cancer survivors and the general population.

Support Care Cancer 2018 02 16;26(2):651-656. Epub 2017 Sep 16.

Centro di Riferimento Oncologico, IRCCS Istituto Nazionale Tumori, Via F. Gallini, 2, 33081, Aviano, PN, Italy.

Purpose: Understanding the quality of life (QoL) of cancer survivors is relevant to both clinical practice and health care policy. The current study compared the QoL profile in this specific population with that of a normative sample for the general population, as well as with those of both healthy and oncological patients normative sub-samples. In addition, associations between the obtained QoL profile and the main socio-demographic and clinical characteristics of the sample were examined.

Methods: Three hundred and ninety-two adult long-term cancer survivors (i.e., people 5 + years from their cancer diagnosis who were free from it and its treatments) were enrolled during follow-up visits and compiled the Short Form 36 Health Survey.

Results: In comparison with the normative data for the adult general population, the present sample showed lower scores in Physical functioning, Role-physical limitation, and Role-emotional limitations (all differences were both statistically and clinically significant); the difference in Vitality was only statistically significant. In all eight SF-36 scales, scores of the present sample were clinically and statistically lower than those of the normative healthy subsample, whereas they were statistically and clinically higher than those of normative subsample which had experienced cancer, except for Role-physical limitation. The QoL profile was associated with gender (p = 0.002), age (p = 0.001), education (p < 0.001), occupational status (p < 0.001), and the presence of other health issues (p < 0.001).

Conclusion: These data support the utility of rehabilitative programs which integrate both healthcare and social interventions. In addition, they encourage the monitoring of the health status of this specific population, within a broad frame which simultaneously takes into consideration health and QoL.
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http://dx.doi.org/10.1007/s00520-017-3880-8DOI Listing
February 2018

Multivalency Increases the Binding Strength of RGD Peptidomimetic-Paclitaxel Conjugates to Integrin α β.

Chemistry 2017 Oct 6;23(58):14410-14415. Epub 2017 Sep 6.

Università degli Studi di Milano, Dipartimento di Chimica, Via C. Golgi 19, 20133, Milan, Italy), Fax: (+39) 02-5031-4072.

This work reports the synthesis of three multimeric RGD peptidomimetic-paclitaxel conjugates featuring a number of α β integrin ligands ranging from 2 to 4. These constructs were assembled by conjugation of the integrin α β ligand cyclo[DKP-RGD]-CH NH with paclitaxel via a 2'-carbamate with a self-immolative spacer, the lysosomally cleavable Val-Ala dipeptide linker, a multimeric scaffold, a triazole linkage, and finally a PEG spacer. Two monomeric conjugates were also synthesized as reference compounds. Remarkably, the new multimeric conjugates showed a binding affinity for the purified integrin α β receptor that increased with the number of integrin ligands (reaching a minimum IC value of 1.2 nm for the trimeric), thus demonstrating that multivalency is an effective strategy to strengthen the ligand-target interactions.
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http://dx.doi.org/10.1002/chem.201703093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656903PMC
October 2017

AXL-associated tumor inflammation as a poor prognostic signature in chemotherapy-treated triple-negative breast cancer patients.

NPJ Breast Cancer 2016 2;2:16033. Epub 2016 Nov 2.

Oncology Experimental Therapeutics, IRCCS Humanitas Clinical and Research Center, Milan, Italy.

A subgroup of triple-negative breast cancer (TNBC) shows epithelial-to-mesenchymal transition (EMT) features, which are sustained by the interaction between cancer cells and tumor-associated macrophages (TAMs). In this study, the clinical relevance of 30 EMT-related kinases and the potential cross-talk with TAMs were investigated in a cohort of 203 TNBC patients treated with adjuvant chemotherapy. The prognostic value of the evaluated markers was validated in two independent cohorts of TNBC patients treated with adjuvant chemotherapy (=95; =137). , we investigated the potential synergism between cancer cells and TAMs. We found that the EMT-related kinase AXL showed the highest correlation with the frequency of CD163-positive macrophages (=0.503; <0.0001). Relapsing TNBC patients presented high expression of AXL (<0.0001) and CD163 (<0.018), but only AXL retained independent prognostic significance in multivariate analysis (relapse-free survival, =0.002; overall survival =0.001). analysis demonstrated that -expressing TNBC cells were able to polarize human macrophages towards an M2-like phenotype, and modulate a specific pattern of pro-tumor cytokines and chemokines. Selective AXL inhibition impaired the activity of M2-like macrophages, reducing cancer cell invasiveness, and restoring the sensitivity of breast cancer cells to chemotherapeutic drugs. These data suggest that the EMT-related kinase AXL overexpressed in cancer cells has prognostic significance, and contributes to the functional skewing of macrophage functions in TNBC. AXL inhibition may represent a novel strategy to target cancer cells, as well as tumor-promoting TAMs in TNBC.
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http://dx.doi.org/10.1038/npjbcancer.2016.33DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515347PMC
November 2016

Immunoexpression of lactoferrin in triple-negative breast cancer patients: A proposal to select a less aggressive subgroup.

Oncol Lett 2017 May 14;13(5):3205-3209. Epub 2017 Mar 14.

Department of Human Pathology of Adult and Evolutive Age 'Gaetano Barresi', Polyclinic 'G. Martino', University of Messina, I-98125 Messina, Italy.

Triple-negative breast cancer (TNBC) indicates a subset of breast carcinomas that does not express estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2). According to the literature, TNBCs are aggressive tumors, characterized by a high incidence of recurrence and a high risk of disease progression. Lactoferrin (LF) is a single-chain, iron-binding glycoprotein of ~700 amino acids, which is involved in a wide range of biological activities, including iron-trafficking and carcinogenesis. The present study aimed to assess LF expression in human TNBC samples and the possible correlation with clinico-pathological parameters associated with biological aggressiveness. LF immunohistochemical expression was investigated in formalin-fixed, paraffin-embedded samples of human TNBC. Cases were analyzed according to an intensity distribution (ID) score, and only those showing an ID score of >2 were considered as positive for LF. LF immunostaining was encountered in 26.15% cases. A significant correlation was found between LF expression and a low Ki-67 labeling index (P=0.040), the absence of recurrence (P=0.010) and alive status (P=0.020). LF may assist in identifying a subset of TNBC with less aggressive biological behavior. The meaning of LF expression in TNBC remains unclear and is controversial. The present findings indicated that LF expression is correlated with a low growth fraction in these tumors. Thus, it is possible that the inhibition of the LF axis may be a valid therapeutic target for TNBC, and this should be confirmed by future studies.
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http://dx.doi.org/10.3892/ol.2017.5859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5431335PMC
May 2017

Tumor Targeting with an isoDGR-Drug Conjugate.

Chemistry 2017 Jun 26;23(33):7910-7914. Epub 2017 May 26.

Dipartimento di Chimica, Università degli Studi di Milano, Via C. Golgi 19, 20133, Milano, Italy.

Herein we report the first example of an isoDGR-drug conjugate (2), designed to release paclitaxel selectively within cancer cells expressing integrin α β . Conjugate 2 was synthesized by connecting the isoDGR peptidomimetic 5 with paclitaxel via the lysosomally cleavable Val-Ala dipeptide linker. Conjugate 2 displayed a low nanomolar affinity for the purified integrin α β receptor (IC =11.0 nm). The tumor targeting ability of conjugate 2 was assessed in vitro in anti-proliferative assays on two isogenic cancer cell lines characterized by different integrin α β expression: human glioblastoma U87 (α β +) and U87 β -KO (α β -). The isoDGR-PTX conjugate 2 displayed a remarkable targeting index (TI=9.9), especially when compared to the strictly related RGD-PTX conjugate 4 (TI=2.4).
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http://dx.doi.org/10.1002/chem.201701844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5488297PMC
June 2017

Clinicopathological and Immunohistochemical Characteristics in Male Breast Cancer: A Retrospective Case Series.

Oncologist 2015 Jun 6;20(6):586-92. Epub 2015 May 6.

Humanitas Clinical and Research Hospital, Rozzano, Milan, Italy; Humanitas Centro Catanese di Oncologia, Catania, Italy; Humanitas Gavazzeni, Bergamo, Italy; Humanitas Mater Domini, Castellanza, Italy.

Background: Due to its rarity, male breast cancer (mBC) remains an inadequately characterized disease, and current evidence for treatment derives from female breast cancer (FBC).

Methods: We retrospectively analyzed the clinicopathological characteristics, treatment patterns, and outcomes of mBCs treated from 2000 to 2013.

Results: From a total of 97 patients with mBC, 6 (6.2%) with ductal in situ carcinoma were excluded, and 91 patients with invasive carcinoma were analyzed. Median age was 65 years (range: 25-87 years). Estrogen receptors were positive in 88 patients (96.7%), and progesterone receptors were positive in 84 patients (92.3%). HER-2 was overexpressed in 13 of 85 patients (16%). Median follow-up was 51.5 months (range: 0.5-219.3 months). Five-year progression-free survival (PFS) was 50%, whereas overall survival (OS) was 68.1%. Patients with grades 1 and 2 presented 5-year PFS of 71% versus 22.5% for patients with grade 3 disease; 5-year OS was 85.7% for patients with grades 1 and 2 versus 53.3% of patients with grade 3. Ki-67 score >20% and adjuvant chemotherapy were also statistically significant for OS on univariate analyses. Twenty-six of 87 patients (29.8%) experienced recurrent disease and 16 of 91 patients (17.6%) developed a second neoplasia.

Conclusion: Male breast cancer shows different biological patterns compared with FBC, with higher positive hormone-receptor status and lower HER-2 overexpression. Grade 3 and Ki-67 >20% were associated with shorter OS.

Implications For Practice: There is little evidence that prognostic features established in female breast cancer, such as grading and Ki-67 labeling index, could be applied to male breast cancer as well. This study found that grade 3 was associated with shorter overall survival and a trend for Ki-67 >20%; this could help in choosing the best treatment option in the adjuvant setting. Many questions remain regarding the impact of HER-2 positivity on survival and treatment with adjuvant anti-HER-2 therapy. Regarding metastatic male breast cancer, the results suggest that common regimens of chemo-, endocrine and immunotherapy used in female breast cancer are safe and effective for men. Male breast cancer patients show a higher incidence of second primary tumors, especially prostate and colon cancers and should therefore be carefully monitored.
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http://dx.doi.org/10.1634/theoncologist.2014-0243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4571775PMC
June 2015

A Novel Anti-CD22 Anthracycline-Based Antibody-Drug Conjugate (ADC) That Overcomes Resistance to Auristatin-Based ADCs.

Clin Cancer Res 2015 Jul 3;21(14):3298-306. Epub 2015 Apr 3.

Research and Early Development, Genentech Inc., South San Francisco, California.

Purpose: We are interested in identifying mechanisms of resistance to the current generation of antibody-drug conjugates (ADC) and developing ADCs that can overcome this resistance.

Experimental Design: Pinatuzumab vedotin (anti-CD22-vc-MMAE) and polatuzumab vedotin (anti-CD79b-vc-MMAE) are ADCs that contain the microtubule inhibitor monomethyl auristatin E (MMAE) attached to the antibody by the protease-cleavable linker maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl (MC-vc-PAB). Early clinical trial data suggest that these ADCs have promising efficacy for the treatment of non-Hodgkin lymphoma (NHL); however, some patients do not respond or become resistant to the ADCs. Anthracyclines are very effective in NHL, but ADCs containing the anthracycline doxorubicin were not clinically efficacious probably due to the low drug potency and inadequate linker technology. The anthracycline analogue PNU-159682 is thousands of times more cytotoxic than doxorubicin, so we used it to develop a new class of ADCs. We used the same MC-vc-PAB linker and antibody in pinatuzumab vedotin but replaced the MMAE with a derivative of PNU-159682 to make anti-CD22-NMS249 and tested it for in vivo efficacy in xenograft tumors resistant to MMAE-based ADCs.

Results: We derived cell lines from in vivo xenograft tumors that were made resistant to anti-CD22-vc-MMAE and anti-CD79b-vc-MMAE. We identified P-gp (ABCB1/MDR1) as the major driver of resistance to the vc-MMAE-based conjugates. Anti-CD22-NMS249 was at least as effective as anti-CD22-vc-MMAE in xenograft models of the parental cell lines and maintained its efficacy in the resistant cell lines.

Conclusions: These studies provide proof of concept for an anthracycline-based ADC that could be used to treat B-cell malignancies that are resistant to vc-MMAE conjugates.
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http://dx.doi.org/10.1158/1078-0432.CCR-14-2035DOI Listing
July 2015

Synthesis and biological evaluation of RGD peptidomimetic-paclitaxel conjugates bearing lysosomally cleavable linkers.

Chemistry 2015 Apr 17;21(18):6921-9. Epub 2015 Mar 17.

Università degli Studi di Milano, Dipartimento di Chimica, Via C. Golgi, 19, 20133, Milan (Italy), Fax: (+39) 02-5031-4072.

Two small-molecule-drug conjugates (SMDCs, 6 and 7) featuring lysosomally cleavable linkers (namely the Val-Ala and Phe-Lys peptide sequences) were synthesized by conjugation of the αvβ3-integrin ligand cyclo[DKP-RGD]-CH2NH2 (2) to the anticancer drug paclitaxel (PTX). A third cyclo[DKP-RGD]-PTX conjugate with a nonpeptide "uncleavable" linker (8) was also synthesized to be tested as a negative control. These three SMDCs were able to inhibit biotinylated vitronectin binding to the purified αVβ3-integrin receptor at nanomolar concentrations and showed good stability at pH 7.4 and pH 5.5. Cleavage of the two peptide linkers was observed in the presence of lysosomal enzymes, whereas conjugate 8, which possesses a nonpeptide "uncleavable" linker, remained intact under these conditions. The antiproliferative activities of the conjugates were evaluated against two isogenic cell lines expressing the integrin receptor at different levels: the acute lymphoblastic leukemia cell line CCRF-CEM (αVβ3-) and its subclone CCRF-CEM αVβ3 (αVβ3+). Fairly effective integrin targeting was displayed by the cyclo[DKP-RGD]-Val-Ala-PTX conjugate (6), which was found to differentially inhibit proliferation in antigen-positive CCRF-CEM αVβ3 versus antigen-negative isogenic CCRF-CEM cells. The total lack of activity displayed by the "uncleavable" cyclo[DKP-RGD]-PTX conjugate (8) clearly demonstrates the importance of the peptide linker for achieving the selective release of the cytotoxic payload.
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http://dx.doi.org/10.1002/chem.201500158DOI Listing
April 2015

Italian Oncological Pain Survey (IOPS): a multicentre Italian study of breakthrough pain performed in different settings.

Clin J Pain 2015 Mar;31(3):214-21

*Anesthesia and Intensive Care & Pain Relief and Supportive Care, La Maddalena Cancer Center, Palermo †Emergency Care, Critical Care Medicine, Pain Medicine and Anesthesiology Department, Tor Vergata University of Rome ‡Anesthesiology, Resuscitation, and Pain Therapy Department, Umberto I Hospital ¶Molecular and Clinical Medicine Medical Oncology, La Sapienza University of Rome #IDI-IRCCS ‡‡‡‡Primary Care, ASL RM F, Rome §Anesthesiology, Resuscitation, and Pain Therapy Department ¶Abdominal Medical Oncology, National Cancer Institute, IRCCS Foundation Pascale ††Medical Oncology, A.O.R.N "A. Cardarelli" Hospital †††Pain Relief, A.O. Dei Colli, Monaldi Hospital, Naples ∥Palliative Care ASL3, Genoa ##Palliative Care, Gerontology and Physical Education Department, E.O. Galliera Hospitals, Genoa **Pain Relief, Palliative Care, Oncology Department, Careggi Hospital, Florence ‡‡Hematology Oncology Center Subalpine (COES), A.O. City Health and Science, Molinette §§§Palliative Care, FARO Foundation, Turin §§IRCCS Foundation National Cancer Institute of Milan, Milan ***Palliative Care, Pain Relief, ASL 13 Mirano Veneto Region ‡‡‡Palliative Care, Pain Relief, Infermi Hospital, Rimini ∥∥∥Medical Oncology, Humanitas Oncology Center of Catania, Catania ¶¶¶Medical Oncology 1, Careggi Hospital, Florence ###Pain Relief, IRCCS Veneto Oncological Institute, Padua ****Pain Relief, Palliative Care, AV3 Macerata Hospital, Macerata ††††Medical Oncology A.O. Treviglio, Bergamo, Italy ∥∥European Palliative Care Research Center, Norwegian University of Science and Technology, Trondheim, Norway.

Objective: A survey of breakthrough pain (BTP) was performed in five palliative care units (PCU), seven oncology departments (ONC), and nine pain clinics (OPC).

Methods: A standard algorithm was used to confirm the diagnosis of BTP of patients refereed to different settings.

Results: 1,412 evaluable cancer patients were enrolled. 53.9% were males and the mean age was 63.7±13.1 years. The mean intensity of background pain was 2.8±0.73. Patients reported 2.4±1.1 BTP episodes/day with a mean intensity of 7.37±1.28. 80.6% patients reported that the BTP had a significant negative impact in everyday life. The majority of patients reported a fast onset of BTP, which was predictable in 50.7% of cases, while BTP with a gradual onset (>10 min) was less predictable (29%) (P=0.001). PCU patients were older, had lower Karnofsky levels, a lower number of BTP episodes/day, a slow onset of BTP onset, and a less predictable BTP. Cancer diagnosis was performed a mean of 23.5 months (SD±32.8) before the assessment. The mean duration of background pain was 3.5 months (SD±3.5), and the mean duration of any analgesic treatment was 2.5 months (SD±3). BTP started a mean of 2.2 months (SD±1.9) before the assessment. Characteristics of BTP were influenced by the course of disease, as well as the duration of background pain and initiation of BTP. Most patients took rapid onset opioids and were satisfied with the treatment. BTP diagnosis was prevalently made by ONC and OPC physicians, and rarely by GPs.

Conclusion: This survey performed by an Italian observatory expert review group, has confirmed that the BTP represents a clinically relevant condition with a negative impact on the patient's quality of life. BTP was detected in all settings involved. A number of factors are associated with the BTP. Also factors regarding the course of disease and setting of care have been assessed. This information may help in stratifying patients or predicting the risk of development of BTP with specific characteristics.
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http://dx.doi.org/10.1097/AJP.0000000000000161DOI Listing
March 2015

Discovery of 2-(cyclohexylmethylamino)pyrimidines as a new class of reversible valosine containing protein inhibitors.

J Med Chem 2014 Dec 12;57(24):10443-54. Epub 2014 Dec 12.

Oncology, Nerviano Medical Sciences S.r.l. , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.

Valosine-containing protein (VCP), also known as p97 or cdc48 in yeast, is a highly abundant protein belonging to the AAA ATPase family involved in a number of essential cellular functions, including ubiquitin-proteasome mediated protein degradation, Golgi reassembly, transcription activation, and cell cycle control. Altered expression of VCP has been detected in many cancer types sometimes associated with poor prognosis. Furthermore, VCP mutations are causative of some neurodegenerative disorders. In this paper we report the discovery, synthesis, and structure-activity relationships of substituted 2-aminopyrimidines, representing a new class of reversible VCP inhibitors. This class of compounds, identified in a HTS campaign against recombinant VCP, has been progressively expanded and manipulated to increase biochemical potency and gain cellular activity.
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http://dx.doi.org/10.1021/jm501313xDOI Listing
December 2014

The interaction of nemorubicin metabolite PNU-159682 with DNA fragments d(CGTACG)(2), d(CGATCG)(2) and d(CGCGCG)(2) shows a strong but reversible binding to G:C base pairs.

Bioorg Med Chem 2012 Dec 3;20(24):6979-88. Epub 2012 Nov 3.

DeFENS-Department of Food, Environmental and Nutritional Sciences, via Celoria 2, 20133 Milano, Italy.

The antitumor anthracycline nemorubicin is converted by human liver microsomes to a major metabolite, PNU-159682 (PNU), which was found to be much more potent than its parent drug toward cultured tumor cells and in vivo tumor models. The mechanism of action of nemorubicin appears different from other anthracyclines and until now is the object of studies. In fact PNU is deemed to play a dominant, but still unclear, role in the in vivo antitumor activity of nemorubicin. The interaction of PNU with the oligonucleotides d(CGTACG)(2), d(CGATCG)(2) and d(CGCGCG)(2) was studied with a combined use of (1)H and (31)P NMR spectroscopy and by ESI-mass experiments. The NMR studies allowed to establish that the intercalation between the base pairs of the duplex leads to very stable complexes and at the same time to exclude the formation of covalent bonds. Melting experiments monitored by NMR, allowed to observe with high accuracy the behaviour of the imine protons with temperature, and the results showed that the re-annealing occurs after melting. The formation of reversible complexes was confirmed by HPLC-tandem mass spectra, also combined with endonuclease P1digestion. The MS/MS spectra showed the loss of neutral PNU before breaking the double helix, a behaviour typical of intercalators. After digestion with the enzyme, the spectra did not show any compound with PNU bound to the bases. The evidence of a reversible process appears from both proton and phosphorus NOESY spectra of PNU bound to d(CGTACG)(2) and to d(CGATCG)(2). The dissociation rate constants (k(off)) of the slow step of the intercalation process, measured by (31)P NMR NOE-exchange experiments, showed that the kinetics of the process is slower for PNU than for doxorubicin and nemorubicin, leading to a 10- to 20-fold increase of the residence time of PNU into the intercalation sites, with respect to doxorubicin. A relevant number of NOE interactions allowed to derive a model of the complexes in solution from restrained MD calculations. The conformation of PNU bound to the oligonucleotides was also derived from the coupling constant values.
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http://dx.doi.org/10.1016/j.bmc.2012.10.033DOI Listing
December 2012

Appropriate management of cutaneous adverse events maximizes compliance with sorafenib treatment: a single-center experience.

Future Oncol 2012 May;8(5):609-15

Day Hospital - UF Oncologia Medica, Humanitas Centro Catanese di Oncologia, via E. Dabormida 64 95126 Catania, Italy.

Aims: This report describes a positive experience of adverse event (AE) management of a multidisciplinary clinical team and 18 patients with late-stage renal cell carcinoma and hepatocellular carcinoma attending the Day Hospital Unit of the 'Centro Catanese di Oncologia Humanitas' (Italy) over a 2-year period.

Methods: The management strategy was based on preventive measures for reducing the development of cutaneous AEs, including pain, risk of infection and patient discomfort, while avoiding the discontinuation or the reduction of the sorafenib dosage.

Results: As of July 2011, eight patients were still under treatment with sorafenib; seven patients experienced cutaneous AEs and two reported severe cutaneous AEs.

Conclusion: Our treatment approach seemed to reduce the incidence and/or severity of AEs, keeping patients in treatment, which is essential for good treatment outcomes.
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http://dx.doi.org/10.2217/fon.12.35DOI Listing
May 2012

NMS-P937, an orally available, specific small-molecule polo-like kinase 1 inhibitor with antitumor activity in solid and hematologic malignancies.

Mol Cancer Ther 2012 Apr 7;11(4):1006-16. Epub 2012 Feb 7.

Nerviano Medical Sciences Srl, Nerviano, Milan, Italy.

Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase considered to be the master player of cell-cycle regulation during mitosis. It is indeed involved in centrosome maturation, bipolar spindle formation, chromosome separation, and cytokinesis. PLK1 is overexpressed in a variety of human tumors and its overexpression often correlates with poor prognosis. Although five different PLKs are described in humans, depletion or inhibition of kinase activity of PLK1 is sufficient to induce cell-cycle arrest and apoptosis in cancer cell lines and in xenograft tumor models. NMS-P937 is a novel, orally available PLK1-specific inhibitor. The compound shows high potency in proliferation assays having low nanomolar activity on a large number of cell lines, both from solid and hematologic tumors. NMS-P937 potently causes a mitotic cell-cycle arrest followed by apoptosis in cancer cell lines and inhibits xenograft tumor growth with clear PLK1-related mechanism of action at well-tolerated doses in mice after oral administration. In addition, NMS-P937 shows potential for combination in clinical settings with approved cytotoxic drugs, causing tumor regression in HT29 human colon adenocarcinoma xenografts upon combination with irinotecan and prolonged survival of animals in a disseminated model of acute myelogenous leukemia in combination with cytarabine. NMS-P937, with its favorable pharmacologic parameters, good oral bioavailability in rodent and nonrodent species, and proven antitumor activity in different preclinical models using a variety of dosing regimens, potentially provides a high degree of flexibility in dosing schedules and warrants investigation in clinical settings.
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http://dx.doi.org/10.1158/1535-7163.MCT-11-0765DOI Listing
April 2012

5-(2-amino-pyrimidin-4-yl)-1H-pyrrole and 2-(2-amino-pyrimidin-4-yl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one derivatives as new classes of selective and orally available Polo-like kinase 1 inhibitors.

Bioorg Med Chem Lett 2012 Jan 23;22(1):96-101. Epub 2011 Nov 23.

Nerviano Medical Sciences srl, Business Unit Oncology, Viale Pasteur 10, 20014 Nerviano, (MI), Italy.

The discovery and characterization of two new chemical classes of potent and selective Polo-like kinase 1 (PLK1) inhibitors is reported. For the most interesting compounds, we discuss the biological activities, crystal structures and preliminary pharmacokinetic parameters. The more advanced compounds inhibit PLK1 in the enzymatic assay at the nM level and exhibit good activity in cell proliferation on A2780 cells. Furthermore, these compounds showed high levels of selectivity on a panel of unrelated kinases, as well as against PLK2 and PLK3 isoforms. Additionally, the compounds show acceptable oral bioavailability in mice making these inhibitors suitable candidates for further in vivo activity studies.
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http://dx.doi.org/10.1016/j.bmcl.2011.11.065DOI Listing
January 2012

Cancer patient-centered home care: a new model for health care in oncology.

Ther Clin Risk Manag 2011 9;7:387-92. Epub 2011 Sep 9.

Medical Oncology Unit, Azienda Sanitaria Provinciale, Siracusa.

Patient-centered home care is a new model of assistance, which may be integrated with more traditional hospital-centered care especially in selected groups of informed and trained patients. Patient-centered care is based on patients' needs rather than on prognosis, and takes into account the emotional and psychosocial aspects of the disease. This model may be applied to elderly patients, who present comorbid diseases, but it also fits with the needs of younger fit patients. A specialized multidisciplinary team coordinated by experienced medical oncologists and including pharmacists, psychologists, nurses, and social assistance providers should carry out home care. Other professional figures may be required depending on patients' needs. Every effort should be made to achieve optimal coordination between the health professionals and the reference hospital and to employ shared evidence-based guidelines, which in turn guarantee safety and efficacy. Comprehensive care has to be easily accessible and requires a high level of education and knowledge of the disease for both the patients and their caregivers. Patient-centered home care represents an important tool to improve quality of life and help cancer patients while also being cost effective.
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http://dx.doi.org/10.2147/TCRM.S22119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3176172PMC
November 2011

NMS-P937, a 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivative as potent and selective Polo-like kinase 1 inhibitor.

Bioorg Med Chem Lett 2011 May 21;21(10):2969-74. Epub 2011 Mar 21.

Nerviano Medical Sciences srl, Business Unit Oncology, Viale Pasteur 10, 20014 Nerviano, MI, Italy.

As part of our drug discovery effort, we identified and developed 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as PLK1 inhibitors. We now report the optimization of this class that led to the identification of NMS-P937, a potent, selective and orally available PLK1 inhibitor. Also, in order to understand the source of PLK1 selectivity, we determined the crystal structure of PLK1 with NMS-P937. The compound was active in vivo in HCT116 xenograft model after oral administration and is presently in Phase I clinical trials evaluation.
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http://dx.doi.org/10.1016/j.bmcl.2011.03.054DOI Listing
May 2011

4,5-Dihydro-1H-pyrazolo[4,3-h]quinazolines as potent and selective Polo-like kinase 1 (PLK1) inhibitors.

Bioorg Med Chem Lett 2010 Nov 17;20(22):6489-94. Epub 2010 Sep 17.

Nerviano Medical Sciences srl, Business Unit Oncology, Viale Pasteur 10, 20014 Nerviano, Milan, Italy.

A series of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives was optimized as Polo-like kinase 1 inhibitors. Extensive SAR afforded a highly potent and selective PLK1 compound. The compound showed good antiproliferative activity when tested in a panel of tumor cell lines with PLK1 related mechanism of action and with good in vivo antitumor efficacy in two xenograft models after i.v. administration.
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http://dx.doi.org/10.1016/j.bmcl.2010.09.060DOI Listing
November 2010

Identification of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as a new class of orally and selective Polo-like kinase 1 inhibitors.

J Med Chem 2010 May;53(9):3532-51

Nerviano Medical Sciences Srl, Oncology, Viale Pasteur 10, 20014 Nerviano, (Mi), Italy.

Polo-like kinase 1 (Plk1) is a fundamental regulator of mitotic progression whose overexpression is often associated with oncogenesis and therefore is recognized as an attractive therapeutic target in the treatment of proliferative diseases. Here we discuss the structure-activity relationship of the 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline class of compounds that emerged from a high throughput screening (HTS) campaign as potent inhibitors of Plk1 kinase. Furthermore, we describe the discovery of 49, 8-{[2-methoxy-5-(4-methylpiperazin-1-yl)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, as a highly potent and specific ATP mimetic inhibitor of Plk1 (IC(50) = 0.007 microM) as well as its crystal structure in complex with the methylated Plk1(36-345) construct. Compound 49 was active in cell proliferation against different tumor cell lines with IC(50) values in the submicromolar range and active in vivo in the HCT116 xenograft model where it showed 82% tumor growth inhibition after repeated oral administration.
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http://dx.doi.org/10.1021/jm901713nDOI Listing
May 2010

In vitro hepatic conversion of the anticancer agent nemorubicin to its active metabolite PNU-159682 in mice, rats and dogs: a comparison with human liver microsomes.

Biochem Pharmacol 2008 Sep 11;76(6):784-95. Epub 2008 Jul 11.

Department of Pharmacology and Anaesthesiology, University of Padova, Largo Meneghetti 2, 35131 Padova, Italy.

We recently demonstrated that nemorubicin (MMDX), an investigational antitumor drug, is converted to an active metabolite, PNU-159682, by human liver cytochrome P450 (CYP) 3A4. The objectives of this study were: (1) to investigate MMDX metabolism by liver microsomes from laboratory animals (mice, rats, and dogs of both sexes) to ascertain whether PNU-159682 is also produced in these species, and to identify the CYP form(s) responsible for its formation; (2) to compare the animal metabolism of MMDX with that by human liver microsomes (HLMs), in order to determine which animal species is closest to human beings; (3) to explore whether differences in PNU-159682 formation are responsible for previously reported species- and sex-related differences in MMDX host toxicity. The animal metabolism of MMDX proved to be qualitatively similar to that observed with HLMs since, in all tested species, MMDX was mainly converted to PNU-159682 by a single CYP3A form. However, there were marked quantitative inter- and intra-species differences in kinetic parameters. The mouse and the male rat exhibited V(max) and intrinsic metabolic clearance (CL(int)) values closest to those of human beings, suggesting that these species are the most suitable animal models to investigate MMDX biotransformation. A close inverse correlation was found between MMDX CL(int) and previously reported values of MMDX LD(50) for animals of the species, sex and strain tested here, indicating that differences in the in vivo toxicity of MMDX are most probably due to sex- and species-related differences in the extent of PNU-159682 formation.
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http://dx.doi.org/10.1016/j.bcp.2008.07.003DOI Listing
September 2008