MILENA PEREZ MAK
Projetos de Pesquisa
Unidades Organizacionais
Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina
13 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 13
- A Patient-Derived, Pan-Cancer EMT Signature Identifies Global Molecular Alterations and Immune Target Enrichment Following Epithelial-to-Mesenchymal Transition(2016) MAK, Milena P.; TONG, Pan; DIAO, Lixia; CARDNELL, Robert J.; GIBBONS, Don L.; WILLIAM, William N.; SKOULIDIS, Ferdinandos; PARRA, Edwin R.; RODRIGUEZ-CANALES, Jaime; WISTUBA, Ignacio I.; HEYMACH, John V.; WEINSTEIN, John N.; COOMBES, Kevin R.; WANG, Jing; BYERS, Lauren AverettPurpose: We previously demonstrated the association between epithelial-to-mesenchymal transition (EMT) and drug response in lung cancer using an EMT signature derived in cancer cell lines. Given the contribution of tumor microenvironments to EMT, we extended our investigation of EMT to patient tumors from 11 cancer types to develop a pan-cancer EMT signature. Experimental Design: Using the pan-cancer EMT signature, we conducted an integrated, global analysis of genomic and proteomic profiles associated with EMT across 1,934 tumors including breast, lung, colon, ovarian, and bladder cancers. Differences in outcome and in vitro drug response corresponding to expression of the pan-cancer EMT signature were also investigated. Results: Compared with the lung cancer EMT signature, the patient-derived, pan-cancer EMT signature encompasses a set of core EMT genes that correlate even more strongly with known EMT markers across diverse tumor types and identifies differences in drug sensitivity and global molecular alterations at the DNA, RNA, and protein levels. Among those changes associated with EMT, pathway analysis revealed a strong correlation between EMT and immune activation. Further supervised analysis demonstrated high expression of immune checkpoints and other druggable immune targets, such as PD1, PD-L1, CTLA4, OX40L, and PD-L2, in tumors with the most mesenchymal EMT scores. Elevated PD-L1 protein expression in mesenchymal tumors was confirmed by IHC in an independent lung cancer cohort. Conclusions: This new signature provides a novel, patient-based, histology-independent tool for the investigation of EMT and offers insights into potential novel therapeutic targets for mesenchymal tumors, independent of cancer type, including immune checkpoints. (C)2015 AACR.
- Multiagent chemotherapy for metastatic adenocarcinoma of the seminal vesicle(2014) GUINDALINI, Rodrigo S. C.; MAK, Milena P.; TAKAHASHI, Tiago K.; TESTA, Laura; DZIK, CarlosAdenocarcinoma of the seminal vesicle is a rare condition, with fewer than 60 cases described in the literature. Most reports highlight the histopathological characteristics of the tumor; however, the role of chemotherapy, especially in the metastatic setting, is poorly described. In this paper, we describe a patient with metastatic disease, who sustained a response to modified FOLFOX6 as first-line therapy. This platinum-based combination therapy seems effective in this scenario and may provide an opportunity for extended survival and relief of symptoms. (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
- Targeting the epidermal growth factor receptor for head and neck cancer chemoprevention(2014) MAK, Milena P.; WILLIAM JR., William N.The epidermal growth factor receptor (EGFR) has been implicated in head and neck squamous cell carcinoma (HNSCC) carcinogenesis. It is currently the only molecular target in head and neck cancers for which there are pharmacologic therapeutic interventions approved by regulatory agencies worldwide to treat advanced disease. Oral pre-malignant lesions have increased EGFR protein expression and increased egfr gene copy number compared to normal mucosa. Oral pre-malignant lesions with overexpression of EGFR or egfr gene copy number gain are at higher risk for malignant transformation. Inhibition of EGFR in pre-clinical models of oral pre-malignancies validates this approach as an effective way to reduce the incidence of oral cancer, and supports investigation of this strategy in the clinic. Clinical trials with EGFR targeted agents, including cetuximab, erlotinib, and vandetanib, are currently under way, some with promising preliminary results. If ultimately shown to reduce the risk of oral cancer, chemoprevention with EGFR inhibitors may significantly reduce morbidity and possibly mortality from HNSCC.
conferenceObject The effects of saliva exosome-like extracellular vesicles from locally advanced OSCC patients on OSCC cell lines(2018) BISPO, Karina A.; GARCIA, Fabyane O. T.; CARVALHO, Tarcia A. C. B.; MAK, Milena P.; CASTRO JR., Gilberto de; PASINI, Fatima S.- Prophylactic Cranial Irradiation for Extensive-Stage Small-Cell Lung Cancer: A Retrospective Analysis(2017) MATUTINO, Adriana; MAK, Milena P.; TAKAHASHI, Tiago K.; BITTON, Rafael C.; NAKAZATO, Denyei; FRAILE, Natalia M. P.; GUIMARAES, Roger G. R.; GABRIELLI, Flavia C. G.; VASCONCELOS, Karina G. M. C.; CARVALHO, Heloisa de A.; CASTRO JR., Gilberto dePurpose Extensive-stage small-cell lung cancer (esSCLC) is an incurable disease and represents a therapeutic challenge because of its poor prognosis. Studies in prophylactic cranial irradiation (PCI) in esSCLC have shown a decreased incidence of symptomatic brain metastases in patients who respond to systemic chemotherapy. However, its effect on overall survival is debatable. We evaluated the benefit of PCI in patients with esSCLC in terms of overall survival, progression-free survival, incidence of brain metastases, recurrence rate, and exposure to postrecurrence therapies. Materials and Methods We retrospectively reviewed electronic charts from patients diagnosed with esSCLC from 2008 to 2014 at our institution. All patients had negative baseline brain imaging before chemotherapy and PCI and received at least 4 cycles of platinum-based chemotherapy in the first-line setting without progressive disease on follow-up. PCI was performed at the discretion of the treating physician. Analyses were based on descriptive statistics. Survival curves were calculated by Kaplan-Meier method. Results Among 46 eligible patients, 16 (35%) received PCI and 30 (65%) did not. Compared with no PCI, PCI led to improved progression-free survival (median, 10.32 v 7.66 months; hazard ratio, 0.4521; 95% CI, 0.2481 to 0.8237; P < .001) and overall survival (median, 20.94 v 11.05 months; hazard ratio, 0.2655; 95% CI, 0.1420 to 0.4964; P < .001) as well as lower incidence of brain metastases (19% v 53%; P = .0273) and higher exposure to second-line chemotherapy (87% v 57%; P = .0479). Conclusion Careful patient selection for PCI can improve not only brain metastases control and higher second-line chemotherapy exposure but also patient survival. (c) 2017 by American Society of Clinical Oncology
- Managing oncology clinical trials during COVID-19 pandemic(2020) ARAI, Roberto J.; V, Camila M. Moniz; CHEN, Andre T. C.; MAK, Milena P.; CHAMMAS, Roger; HOFF, Paulo M.Sao Paulo city is the epicenter of the Brazilian COVID-19 pandemic. The Instituto do Cancer do Estado de Sao Paulo is currently conducting 161 multinational sponsored trials plus 116 in house studies in the oncologic population. There are 242 currently active participants and 180 patients in follow-up. The management of the tightly controlled environment of clinical research becomes a challenge, and the Food and Drug Administration set of priority recommendations for patient safety while maintaining study integrity. Fast adaptations are necessary, and actions coalesce to participant protection from COVID-19. We pointed out critical processes for adjustments, and we believe that our experience may help other academic health centers.
- Percutaneous transhepatic biliary drainage (PTBD) in patients (pts) with advanced solid malignancies: Clinical outcomes and prognostic factors(2012) CROSARA, Marcela Alves Teixeira; MAK, Milena P.; MARQUES, Daniel Fernandes; CAPARELI-AZEVEDO, Fernanda C.; HOFF, Paulo Marcelo
conferenceObject REFERRAL OF LUNG CANCER PATIENTS TO SPECIALIZED CLINICAL ONCOLOGY CARE: INSTITUTO DO CANCER DO ESTADO DE SAO PAULO 2010-2011(2012) CAIRES-LIMA, Rafael; TAKAHASHI, Tiago K.; MAK, Milena P.; ROITBERG, Felipe S. R.; TEIXEIRA, Carlos H. A.; MESQUITA, Cristiane S.; MARINI, Andrea M.; MARTINS, Renata E.; TAKAGAKI, Tereza Y.; ARAUJO, Pedro N.; FEHER, Olavo; HOFF, Paulo M.; CASTRO JR., Gilberto DeBackground: Lung cancer is the leading cause of death from malignancy in Western countries. To achieve better outcomes and improve quality of care, it is essential to know both patients and disease characteristics. Here we aim to describe epidemiological and tumor characteristics and their impact on survival outcomes, of patients admitted at Instituto do Câncer de Estado de São Paulo (ICESP) between January 2010 and July 2011. Methods: It is a retrospective, descriptive, and uninstitutional study, of patients diagnosed histologically with lung cancer, consecutively admitted at ICESP between January 2010 and July 2011. Overall survival was the main endpoint. Frequencies were compared using chi-square test. Survival was estimated using the Kaplan-Meier methods, and the curves were compared by the log-rank test. This study was approved by the local IRB. Results and Conclusion: 232 patients (pts) were included in this analysis: median age 65y (24-91), 57% male, 56% ECOG 0 - 1, and 83% previous or current smokers. Non small cell lung cancer (NSCLC) was the most common histologic type (213 pts, 92%). Small cell lung cancer (SCLC) was diagnosed in 18 pts (7.6%) and only one (0.4%) was a case of a carcinoid tumor. Regarding NSCLC histologic subtypes, adenocarcinoma was the most common (130 pts, 61%), followed by squamous cell carcinoma (63 pts, 30%) and large cell carcinoma (5 pts, 2%). In 17 pts (7%), it was not possible to determine the subtype, even with immunohistochemistry. In terms of staging, 155 pts (71%) with NSCLC presented metastatic disease (stage IV) at diagnosis, 27 pts (12%) were staged as IIIB, 15 pts (10%) IIIA, 8 pts (3.5%) II and 8 pts (3.5%) I. Among patients with SCLC, six (33%) had localized disease (LD) and 12 (67%) had extensive disease (ED). Analyzing only stage IV NSCLC pts, 123 (79%) were treated with first line chemotherapy, 56 (36%)with second line and 13 (8%) with third line systemic therapies; ECOG 0 - 2 NSCLC pts were more likely to be exposed to second-line therapies (46% vs 36%; p = 0.0002). In a median follow-up of 9.5 mo, median overall survival (mOS) was 9 mo for all pts in this analysis. Regarding NSCLC, in patients with stage I and II mOS was not reached (100% and 68% in 2 years for stage I and II, respectively). In patients with stage IIIA, IIIB and IV, the median OS was 15.2, 11.4 and 7 mo, respectively (p-trend = 0.0002). According to ECOG-PS, mOS was 11.3, 6.3, 4.1, and 2.2 mo for NSCLC pts with ECOG 1, 2, 3 and 4, respectively (p-trend < 0.0001). For SCLC pts, mOS was 12.9 mo among those with LD versus 4.9 mo in ED (HR 3.1; 95% CI 1.1 - 8.6; p = 0.02). Lung cancer survival rate remains poor. As expected, clinical stage and performance status were important prognostic factors. Primary prevention strategies (quitting smoking) and early diagnosis (screening) may be useful in this scenario.conferenceObject EGFR ACTIVATING MUTATIONS IN NSCLC: IMPORTANCE OF ROUTINE TESTING(2012) TAKAHASHI, Tiago K.; SOARES, Ibere C.; MARINI, Andrea M.; MAK, Milena P.; TEIXEIRA, Carlos H.; ROITBERG, Felipe S. R.; TAKAGAKI, Teresa Y.; MARTINS, Renata E.; MESQUITA, Cristiane; HOFF, Paulo M. G.; CASTRO JR., GilbertoBackground: EGFR activating mutations in NSCLC confer better prognosis and are also predictive of response to both chemotherapy and EGFR-tyrosine kinase inhibitors. Therefore, EGFR genotyping in NSCLC patients (pts) is very helpful in treatment decision. Here we report the first 25 pts whose tumors samples were tested for EGFR activating mutations in our Institution. Methods: It is an observational study on all consecutively tested NSCLC samples from pts treated at ICESP. Briefly, all samples were formalin-fixed and paraffin-embedded. Tumor areas were selected and macrodissected, followed by whole DNA extraction and amplification by PCR. DNA sequencing (exons 18, 19, 20 and 21) was performed by Sanger´s methodology. Frequencies were compared by Fisher´s exact test. Results and Conclusion: Results: 25 tumor samples were tested from Aug/2011 up to now: 20 pts were caucasian, 13 were male, 14 ex-smoker, 10 never smoker; 15 pts ECOG-PS 0-1 and 5 PS 2. Regarding histologic subtype, 22 were classified as adenocarcinoma and 2 SCC. Staging: 3 IIIA, 2 IIIB and 20 IV. Activating mutations were detected in 6 pts (24%): 4 in exon 19 (del 19), 1 in exon 21 (L858R) and in 1 pt two mutations were found (T790M and L858R). The frequency of these activating mutations was not related to gender (p=0.378), race (p=0.540) or smoking habits (p=0.350). In a short follow-up of 6 mo., no deaths occurred in pts whose samples were positive for activating mutations. Conclusions: In this very selected population, the frequency of EGFR activating mutations was 24%, with no correlation with gender, race or smoking habits. This reinforces the importance of testing EGFR activating mutations in all pts with lung adenocarcinoma. Disclosure: No significant relationships.- Is there still a role for induction chemotherapy in locally advanced head and neck cancer?(2014) MAK, Milena P.; GLISSON, Bonnie S.Purpose of reviewDespite decades of research, the role of induction chemotherapy (ICT) in the treatment of locally advanced head and neck squamous cell carcinoma remains controversial. When nonsurgical approaches are preferred, chemoradiation (CRT) is the standard of care. However, ICT continues to be investigated, as it can cytoreduce tumors, improve radiotherapy feasibility and tolerability, select patients for organ preservation with radiation, and decrease the risk of distant metastasis.Recent findingsHerein, we review the recent randomized trials that investigated the role of taxanes in ICT, compared with surgery or CRT alone. A metaanalysis of older trials comparing taxane-containing ICT to cisplatin and 5-fluorouracil is discussed. In addition, long-term results from Radiation Therapy Oncology Group 91-11, a three-arm trial of larynx preservation approaches, are discussed, as well as a recent trial of sequential CRT for larynx preservation. As in previous randomized trials, no survival benefit for ICT was demonstrated. However, two studies showed a reduced risk of distant metastasis in advanced nodal stage patients. As regards larynx preservation, ICT followed by radiation alone in responders to chemotherapy remains an effective option.SummaryICT is still controversial and in general, should remain investigational. An exception may be its use in a larynx preservation approach, albeit with a lower crude larynx preservation rate compared with CRT. The results of recent trials provide rationale and support hypothesis generation for future research, which should focus on subsets of patients most likely to benefit, for example, high nodal stage. It will be critical to study human papillomavirus (HPV)-associated oropharynx cancer separately or, at least, stratify by HPV status given its influence on prognosis and attendant implications for statistical design.