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M. Villalona-Calero



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    MO15 - Novel Genes and Pathways (ID 89)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO15.05 - Oncogenic ARAF mutation in lung adenocarcinoma (ID 2860)

      16:15 - 17:45  |  Author(s): M. Villalona-Calero

      • Abstract
      • Presentation
      • Slides

      Background
      Targeted cancer therapies often induce “outlier” responses in molecularly defined patient subsets.

      Methods
      One patient with advanced-stage lung adenocarcinoma, who was treated with oral sorafenib, demonstrated a complete clinical and radiographic remission for five years. Whole genome sequencing (WGS) and RNA sequencing (RNA-seq) on primary tumor and normal samples from this patient was performed.

      Results
      We identified a somatic mutation, ARAF S214C, present in the cancer genome and expressed at high levels. Additional mutations affecting this residue of ARAF and a nearby residue in the related kinase RAF1 were demonstrated across 1% of an independent cohort of lung adenocarcinoma cases. The ARAF mutants were shown to transform immortalized human airway epithelial cells and were associated with in vitro sorafenib sensitivity.

      Conclusion
      These results suggest that mutant ARAF may be a novel oncogenic driver in lung adenocarcinoma and an indicator of sorafenib response.

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-026 - Final Results of a Phase 2 Trial of the Oncolytic Virus Reovirus Serotype 3-Dearing Strain (REOLYSIN®) in Metastatic NSCLC Patients with a Ras-activated Pathway. (ID 1994)

      09:30 - 16:30  |  Author(s): M. Villalona-Calero

      • Abstract

      Background
      Reovirus is a naturally occurring virus which preferentially infects and causes oncolysis in tumor cells with a Ras-activated pathway. In preclinical studies, reovirus induces cell cycle arrest, acting synergistically with standard cytotoxic agents. We have hypothesized that patients with EGFR-mutated, EGFR-amplified, BRAF or Kras-mutated NSCLC should all have a common downstream activated Ras pathway and should be susceptible to treatment with reovirus.

      Methods
      We conducted a Fleming, single-arm, phase II study to evaluate safety and the objective response rate (primary end-points), as well as 6-month progression-free and 1 year survival (secondary end-points) of metastatic NSCLC patients treated with reovirus in combination with paclitaxel/carboplatin (P/C). Eligible patients had ECOG PS 0-2, adequate organ function, no prior chemotherapy for metastatic disease, and tumors with the specified above genotype, as per CLIA certified laboratory testing. Prior adjuvant chemotherapy, or erlotinib/gefitinib for pts with EGFR-mutant tumors was permitted. Patients received Reovirus (3 x 10[10 ]TCID~50~) intravenously daily on days 1-5, in combination with P/C at initial doses of P 200 mg/m[2] and C AUC 6, on day 1 of each 21-day cycle. Due to exacerbation of prior colitis and febrile neutropenia (1 each) in the first two pts, doses were subsequently reduced to P 175 mg/m m[2] and C AUC 5.

      Results
      Overall, 37 patients received 209 cycles (per pt median 4, range 1 to 18). Grade 3-4 toxicity included febrile neutropenia (3 pts), G3 diarrhea (2 pts), G3 anemia (8 pts), fatigue in 6 pts (5 G3, 1 G4), nausea/vomiting and thrombocytopenia (2 pts each), electrolyte abnormalities, and single G3 episodes of arthralgia and transaminitis. Molecular tumor demographics included: 20 Kras (2 G12A, 9 G12C, 1 G12D, 1 G12R, 1 G12S, 3 G12V, 1 G13C, 1 G13R, 1 G12C/V double mutant), 3 EGFR exon 19, 4 BRAF V600E mutations, and 10 EGFR amplified only. Response evaluation showed 11 RECIST partial responses (30%) (EGFR amp 5, BRAF 2, Kras 3, EGFR mut 1), 21 SD, and 4 PD. PFS (by CT and PET) at 6 months for 36 patients with enough follow up to date is 36%, with PET results influencing switching to second line therapy in several patients with SD by CT. Sixteen patients received 6 or more cycles. One year survival was 53%.

      Conclusion
      Reovirus can be administered safely in combination with P/C and patient selection by Ras-activated pathway is feasible in the clinical setting. Overall clinical efficacy is encouraging. Randomized evaluation is planned.

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    P2.01 - Poster Session 2 - Cancer Biology (ID 145)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.01-004 - Type of P53 mutation influences oncogenic potential and spectrum of associated K-ras mutations in lung specific transgenic mice. (ID 1972)

      09:30 - 16:30  |  Author(s): M. Villalona-Calero

      • Abstract

      Background
      p53 mutations have been categorized as type I (contact) and type II (conformational) mutations. Differential effects of type I vs. type II p53 mutations in spontaneous lung tumor formation, and their relationship with secondary genetic alterations have not been previously reported. .

      Methods
      We evaluated the potential of two common type I (273H) and type II (175H) mutations under the transcriptional control of the human surfactant protein C (SP-C) promoter to induce lung tumors in transgenic mice. Necropsies of 138 non-transgenic, 207 SP-C-p53-273H and 171 SPC-p53-175H transgenic mice in progressive age cohorts were performed.

      Results
      Ninety-one tumors, all adenocarcinomas, were observed; 8 (5.8%), 37 (17.9%) and 46 (26.9%) in non-transgenics, p53-273H and p53-175H, respectively (non-transgenic vs. 273H, p=0.010; non-transgenic vs. 175H, p= 0.0003; logistic regression). Type II p53 mutants had an earlier onset of tumors; 23 of 98 p53-175H mice developed tumors before the age of 13 months, compared to 7 of 108 p53-273H mice (p=0.012, logistic regression). K-ras mutations occurred in a substantial proportion (21 of 50, 42%) of murine lung tumors sequenced. For both the non-transgenic and the p53-273H transgenics, tumor K-ras codon 12-13 mutations occurred after 13 months with a peak incidence at 16–18 months. However, for the p53-175H transgenics K-ras codon 12-13 mutations were observed as early as six months, with a peak incidence between the ages of 10-12 months. Codons 12-13 were the predominant location in p53-175H transgenics (6 of 7), whereas codon 61 (6 of 10) was more common in p53-273H transgenics.

      Conclusion
      The observation of accelerated tumor onset, early appearance and high frequency of K-ras codon 12-13 mutations in type II p53-175H mice confirms the enhanced oncogenic function of conformational p53 mutations, and the gains in early genetic instability for tumors containing these mutations compared to contact mutations. These data would suggest that not only the presence, but also the type of p53 mutations in human lung cancer should be considered when evaluating prognosis and developing treatment strategies for this malignancy. These mice develop a single-lung tumor that is easy to follow with CT imaging. Thus, these animal models provide a framework for evaluation of the effects of these mutations on response to standard and novel anticancer treatment interventions.