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Cervical cancer is a public health problem and the molecular mechanisms underlying radioresistance are still poorly understood. Here, we evaluated the modulation of key molecules involved in cell proliferation, cell cycle and DNA repair in cervical cancer cell lines (CASKI and C33A) and in malignant tissues biopsied from 10 patients before and after radiotherapy. The expression patterns of epidermal growth factor receptor (EGFR), excision repair cross-complementation group 1 (ERCC1) and p53 were evaluated in cancer cell lines by quantitative PCR and western blotting, and in human malignant tissues by immunohistochemistry. The mutation status of TP53 gene was evaluated by direct sequencing. Among cell lines, absent or weak modulations of EGFR, ERCC1 and p53 were observed after exposure to 1.8 Gy. Conversely, increased expressions of p53 (5/10 patients; P=0.0239), ERCC1 (5/10 patients; P=0.0294) and EGFR (4/10 patients; P=0.1773) were observed in malignant tissues after radiotherapy with the same radiation dose. TP53 mutations were found only in one patient. Here we show that a single dose of radiotherapy induced EGFR, ERCC1 and p53 expression in malignant tissues from cervical cancer patients but not in cancer cell lines, highlighting the gap between in vitro and in vivo experimental models. Studies on larger patient cohorts are needed to allow an interpretation that an upregulation of p53, EGFR and ERCC1 may be part of a radioresistance mechanism.

Cervix cancer (CC) represents the fourth most common cancer in women. Treatment involving cisplatin and radiotherapy has been the standard for locally advanced disease. Everolimus inhibits the aberrant activity of mTOR that is part of carcinogenesis in CC. Further everolimus inactivates the HPV E7 oncoprotein and inhibits its proliferation. Preclinical models have suggested that everolimus sensitizes tumoral cells and vasculature to cisplatin and radiotherapy. In a 3 + 3 design, the trial aimed to treat three dose levels of at least three patients with daily doses of everolimus (2.5, 5 and 10 mg/day), cisplatin and radiotherapy delivered in a 9-week interval in CC patients, stage IIB, IIIA or IIIB. Patients received everolimus from day −7 up to the last day of brachytherapy. Primary objective was to evaluate safety, toxicity and the maximum-tolerated dose (MTD) of everolimus in association with cisplatin and radiotherapy. Pharmacokinetic (PK) parameters and response rates were analyzed as secondary objectives. Thirteen patients were enrolled, 6 at 2.5 mg, 3 at 5 mg and 4 at 10 mg. Four patients did not complete the planned schedule, 1 at 2.5 mg presented grade 4 acute renal failure interpreted as dose-limiting toxicity (DLT) and 3 at 10 mg: 1 with disease progression, and 2 with DLTs—1 grade 3 rash and 1 grade 4 neutropenia. PK results were characterized by dose-dependent increases in AUC and C max. The MTD of everolimus in combination with cisplatin and radiotherapy has been defined as 5 mg/day. The data regarding safety and response rates support further studies.

Background: Cervical cancer (CC) represents the second most commonly diagnosed cancer in women. The combined treatment involving C and R has been the standard treatment for stages IIB-IIIB. However the results are still disappointing with 5-year survival rates lower than 50%. There is a great need to explore new strategies in order to improve the prognosis of these patients. E inhibits the mammalian target of rapamycin (mTOR). The high aberrant activity of mTOR complexes is part of the underlying cause of carcinogenesis in CC. Further E inactivates the oncoprotein E7 (essential in the carcinogenesis of HPV) and inhibits its proliferation. Preclinical models have suggested that mTOR inhibitors sensitize tumoral cells and vasculature to C and R effects. Therefore mTOR inhibition may represent a promising treatment approach in CC. Methods: The primary objective of this trial is to evaluate the safety, toxicity (according to NCI CTCAE 3.0) and the maximum tolerated dose (MTD) of E in association to C and R in the treatment of locally advanced CC. The secondary objectives are to quantify PK and PD parameters, and to evaluate the response rate (using RECIST 1.1). In a modified Fibonacci design the trial aims to evaluate three cohorts of at least three patients treated with daily escalating doses of E (2.5/5/10 mg) in association with C (40 mg/m2 of body surface per week, for 5 weeks during teletherapy) and R (teletherapy - 4.500 cGy in 25 fractions, followed by 4 fractions of 600 cGy weekly of brachytherapy - B) in squamous cell cervical carcinoma patients stage IIB to IIIB. Patients are treated with E from day -7 to day 0 (one week before the C+R starting) up to the last day of B. Results: As of December 01, 2013, 13 patients were enrolled, 6 in the cohort #1, 3 in the cohort #2 and 4 in the cohort #3. Two patients did not completed the planned schedule, one at dose level of 2,5 mg presented grade 4 acute renal failure interpreted as dose limiting toxicity (DLT) and one at dose level of 10 mg with disease progression. Grade 3 toxicity occurred in cohorts #1 and #2 as follows: lymphopenia in 6 patients, neutropenia in 3 patients and leukopenia in 1 patient. Three patients in the cohort #3 are still on treatment. PK and PD studies will be performed together, after collection of the entire set of samples. Conclusions: The end of treatment of the last cohort is due to February 2014, when the MTD will be established. To the best of our knowledge this is the first study of everolimus, cisplatin and pelvic radiotherapy combination. Citation Format: Carlos Gil Ferreira, Flávia V. Guerra Alves, Rachele Grazziotin, Felipe Erlich, Giulliana Moralez, Michel P. Carneiro, Mariane Fontes Dias, Andréia C. de Melo. A Phase I study of oral administration of mTOR inhibitor everolimus (E) in association with cisplatin (C) and radiotherapy (R) for the treatment of locally advanced cervix cancer (LACC) - PHOENIX I. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT403. doi:10.1158/1538-7445.AM2014-CT403