Peter Dottino

Icahn School of Medicine at Mount Sinai, Manhattan, New York, United States

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Publications (11)32.88 Total impact

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    ABSTRACT: High-grade serous ovarian cancer (HGSOC) that is resistant to platinum-based chemotherapy has a particularly poor prognosis. Response to platinum has both prognostic survival value and dictates secondary treatment strategies. Using transcriptome analysis, we sought to identify differentially expressed genes/pathways based on a tumor's platinum response for discovering novel predictive biomarkers.
    Gynecologic oncology. 07/2014;
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    ABSTRACT: Retrospective studies have demonstrated that nearly 50% of patients with ovarian cancer with normal cancer antigen 125 (CA125) levels have persistent disease; however, prospectively distinguishing between patients is currently impossible. Here, we demonstrate that for one patient, with the first reported fibroblast growth factor receptor 2 (FGFR2) fusion transcript in ovarian cancer, circulating tumor DNA (ctDNA) is a more sensitive and specific biomarker than CA125, and it can also inform on a candidate therapeutic. For a 4-year period, during which the patient underwent primary debulking surgery and chemotherapy, tumor recurrences, and multiple chemotherapeutic regimens, blood samples were longitudinally collected and stored. Whereas postsurgical CA125 levels were elevated only three times for 28 measurements, the FGFR2 fusion ctDNA biomarker was readily detectable by quantitative real-time reverse transcription-polymerase chain reaction (PCR) in all of these same blood samples and in the tumor recurrences. Given the persistence of the FGFR2 fusion, we treated tumor cells derived from this patient and others with the FGFR2 inhibitor BGJ398. Only tumor cells derived from this patient were sensitive to FGFR2 inhibitor treatment. Using the same methodologic approach, we demonstrate in a second patient with a different fusion that PCR and agarose gel electrophoresis can also be used to identify tumor-specific DNA in the circulation. Taken together, we demonstrate that a relatively inexpensive, PCR-based ctDNA surveillance assay can outperform CA125 in identifying occult disease.
    Neoplasia (New York, N.Y.) 01/2014; 16(1):97-103. · 5.48 Impact Factor
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    ABSTRACT: The aim of this study is to determine the role of liver metastatectomy in the morbidity and survival of patients with recurrent ovarian carcinoma. We retrospectively reviewed the records of all patients who had undergone hepatic resection for liver metastases from ovarian carcinoma at the time of cytoreductive surgery at our institution from 1988 to 2012. The Kaplan-Meier method was used for survival analysis. A total of 76 patients met the inclusion criteria and had undergone liver resection as part of cytoreductive surgery for ovarian carcinoma during the study period. Of these 76 patients, 27 underwent liver resection at the time of secondary cytoreduction, and these patients that are the focus of this analysis. Median overall survival for the study group from the time of diagnosis to the last follow-up or death was 56 months (range, 12-249 months). Twenty died of the disease with an overall median survival of 12 months from the time of the liver resection (2-190 months), and 7 patients were alive with the disease at the time of the last follow-up. Based on Kaplan-Meier survival analysis, the factors associated with the longest survival after the liver resection (2-190 months) were the interval from the primary surgery of less than 24 months versus more than 24 months (P = 0.044) and secondary cytoreduction to residual disease of less than 1 cm (P = 0.014). Based on our analysis of a single institution's series of ovarian cancer patients with hepatic metastasis, liver resection is feasible and safe and should be considered as an option in selected patients at the time of secondary cytoreduction.
    International Journal of Gynecological Cancer 01/2014; 24(1):70-4. · 1.94 Impact Factor
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    ABSTRACT: We sought to identify candidate serum biomarkers for the detection and surveillance of EOC. Based on RNA-Seq transcriptome analysis of patient-derived tumors, highly expressed secreted proteins were identified using a bioinformatic approach. RNA-Seq was used to quantify papillary serous ovarian cancer transcriptomes. Paired end sequencing of 22 flash frozen tumors was performed. Sequence alignments were processed with the program ELAND, expression levels with ERANGE and then bioinformatically screened for secreted protein signatures. Serum samples from women with benign and malignant pelvic masses and serial samples from women during chemotherapy regimens were measured for IGFBP-4 by ELISA. Student's t Test, ANOVA, and ROC curves were used for statistical analysis. Insulin-like growth factor binding protein (IGFBP-4) was consistently present in the top 7.5% of all expressed genes in all tumor samples. We then screened serum samples to determine if increased tumor expression correlated with serum expression. In an initial discovery set of 21 samples, IGFBP-4 levels were found to be elevated in patients, including those with early stage disease and normal CA125 levels. In a larger and independent validation set (82 controls, 78 cases), IGFBP-4 levels were significantly increased (p < 5 × 10-5). IGFBP-4 levels were ~3× greater in women with malignant pelvic masses compared to women with benign masses. ROC sensitivity was 73% at 93% specificity (AUC 0.816). In women receiving chemotherapy, average IGFBP-4 levels were below the ROC-determined threshold and lower in NED patients compared to AWD patients. This study, the first to our knowledge to use RNA-Seq for biomarker discovery, identified IGFBP-4 as overexpressed in ovarian cancer patients. Beyond this, these studies identified two additional intriguing findings. First, IGFBP-4 can be elevated in early stage disease without elevated CA125. Second, IGFBP-4 levels are significantly elevated with malignant versus benign disease. These findings provide the rationale for future validation studies.
    Journal of Ovarian Research 01/2012; 5(1):3. · 2.43 Impact Factor
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    ABSTRACT: RNA-Seq allows a theoretically unbiased analysis of both genome-wide transcription levels and mutation status of a tumor. Using this technique we sought to identify novel candidate therapeutic targets expressed in epithelial ovarian cancer (EOC). Specifically, we sought candidate invasion/migration targets based on expression levels across all tumors, novelty of expression in EOC, and known function. RNA-Seq analysis revealed the high expression of CD151, a transmembrane protein, across all stages of EOC. Expression was confirmed at both the mRNA and protein levels using RT-PCR and immunohistochemical staining, respectively. In both EOC tumors and normal ovarian surface epithelial cells we demonstrated CD151 to be localized to the membrane and cell-cell junctions in patient-derived and established EOC cell lines. We next evaluated its role in EOC dissemination using two ovarian cancer-derived cell lines with differential levels of CD151 expression. Targeted antibody-mediated and siRNA inhibition or loss of CD151 in SKOV3 and OVCAR5 cell lines effectively inhibited their migration and invasion. Taken together, these findings provide the first proof-of-principle demonstration for a next generation sequencing approach to identifying candidate therapeutic targets and reveal CD151 to play a role in EOC dissemination.
    Journal of Ovarian Research 01/2012; 5:4. · 2.43 Impact Factor
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    ABSTRACT: The shape of nuclei in many adherent cultured cells approximates an oblate ellipsoid, with contralateral flattened surfaces facing the culture plate or the medium. Observations of cultured cell nuclei from orthogonal perspectives revealed that nucleoporin p62 (NUP62) and nucleoporin 214 (NUP214) are differentially distributed between nuclear pore complexes on the flattened surfaces and peripheral rim of the nucleus. High resolution stimulated emission depletion (STED) immunofluorescence microscopy resolved individual NPCs, and suggested both heterogeneity and microheterogeneity in NUP62 and NUP214 immunolabeling among in NPC populations. Similar to nuclear domains and interphase chromosome territories, architectural diversity and spatial patterning of NPCs may be an intrinsic property of the nucleus that is linked to the functions and organization of underlying chromatin.
    PLoS ONE 01/2012; 7(4):e36137. · 3.73 Impact Factor
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    ABSTRACT: Phenotypic diversity arises in tumors just as it does in developing organisms, and tumor recurrence frequently manifests from the selective survival of divergent drug-resistant cells. Although the expanding tumor cell population may be successfully targeted, drug-resistant cells may persist and sustain the tumor or enter dormancy before igniting a future relapse. Herein, we show that partial knockdown of nucleoporin p62 (NUP62) by small-interfering RNA confers cisplatin resistance to cultured high-grade ovarian carcinoma cells. Treatment with NUP62 small-interfering RNA and cisplatin leaves resistant cells in a state of dormancy; some dormant cells can be induced to proliferate by transient induction of NUP62 expression from an ectopic expression construct. In addition to suggesting functional links between nuclear pore complex architecture and cancer cell survival, the culture system provides a novel experimental window into the dynamics of tumor cell drug resistance and dormancy.
    American Journal Of Pathology 11/2011; 180(1):375-89. · 4.60 Impact Factor
  • John A Martignetti, Peter R Dottino
    Gynecologic Oncology 05/2011; · 3.93 Impact Factor
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    ABSTRACT: ABSTRACT: Glutathione peroxidase 3 (GPX3) is a selenocysteine-containing antioxidant enzyme that reacts with hydrogen peroxide and soluble fatty acid hydroperoxides, thereby helping to maintain redox balance within cells. Serum levels of GPX3 have been found to be reduced in various cancers including prostrate, thyroid, colorectal, breast and gastric cancers. Intriguingly, GPX3 has been reported to be upregulated in clear cell ovarian cancer tissues and thus may have implications in chemotherapeutic resistance. Since clear cell and serous subtypes of ovarian cancer represent two distinct disease entities, the aim of this study was to determine GPX3 levels in serous ovarian cancer patients and establish its potential as a biomarker for detection and/or surveillance of papillary serous ovarian cancer, the most frequent form of ovarian tumors in women. Serum was obtained from 66 patients (median age: 62 years, range: 22-89) prior to surgery and 65 controls with a comparable age-range (median age: 53 years, range: 25-83). ELISA was used to determine the levels of serum GPX3. The Mann Whitney U test was performed to determine statistical significance between the levels of serum GPX3 in patients and controls. Serum levels of GPX3 were found to be significantly lower in patients than controls (p = 1 × 10-2). Furthermore, this was found to be dependent on the stage of disease. While levels in early stage (I/II) patients showed no significant difference when compared to controls, there was a significant reduction in late stage (III/IV, p = 9 × 10-4) and recurrent (p = 1 × 10-2) patients. There was a statistically significant reduction in levels of GPX3 between early and late stage (p = 5 × 10-4) as well as early and recurrent (p = 1 × 10-2) patients. Comparison of women and controls stratified to include only women at or above 50 years of age shows that the same trends were maintained and the differences became more statistically significant. Serum GPX3 levels are decreased in women with papillary serous ovarian cancer in a stage-dependent manner and also decreased in women with disease recurrence. Whether this decrease represents a general feature in response to the disease or a link to the progression of the cancer is unknown. Understanding this relationship may have clinical and therapeutic consequences for women with papillary serous adenocarcinoma.
    Journal of Ovarian Research 01/2011; 4:18. · 2.43 Impact Factor
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    ABSTRACT: A central challenge facing gynecologic oncology is achieving personalized care in ovarian cancer treatment. The current ovarian cancer classification scheme distinguishes tumors based on histopathologic subtype, grade, and surgical stage. Recent molecular investigations have highlighted distinguishing genetic features of certain tumors within a given category, and given the rapid pace of technologic advancement combined with plummeting costs for complete genomic sequencing this classification will markedly improve. Clinical studies have begun to explore the influence of currently known distinctions on the natural history of the disease, most recently with particular attention to the BRCA1 status of tumors. Mutations in the BRCA1 gene have long been known to increase a woman's risk of developing ovarian cancer. As has been shown, BRCA1-associated ovarian cancers may be associated with characteristic differences in therapeutic response and overall survival, and further defining these subsets may become instrumental in clinical decision-making. Therefore, given the eightfold difference (5-40%) in reported frequency of BRCA1 inactivation by methylation in the pioneering studies in the field, a critical re-appraisal of the literature, techniques, samples used, and interpretations of BRCA1 inactivation is warranted along with a review of the more recent and comprehensive molecular studies.
    Gynecologic Oncology 11/2010; 119(2):376-83. · 3.93 Impact Factor
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    ABSTRACT: Recent advances in the surgical management of early cervical cancer, including abdominal, laparoscopic, vaginal, and robotic approaches to radical hysterectomy as well as fertility-sparing radical trachelectomy, are reviewed. The nerve-sparing abdominal radical hysterectomy technique allows for a significant reduction in postoperative bladder morbidity. Radical vaginal hysterectomy with laparoscopic lymph node dissection is a well-recognized technique that offers excellent cure rates without abdominal entry as well as reduced postoperative febrile and gastrointestinal morbidity. Total laparoscopic radical hysterectomy is a minimally invasive alternative to the traditional abdominal radical hysterectomy approach and yields a comparable safety profile with a significant reduction in blood loss and hospital stay. Robotic surgery is becoming more widely accepted in the management of gynecologic cancers, including radical hysterectomy for early cervical cancer. Young women desiring to bear children in the future may be candidates for fertility preservation options, and the radical trachelectomy operation has been described and performed with abdominal, vaginal, laparoscopic, and robotic techniques. There are a number of surgical options for the treatment of women with early cervical cancer. The feasibility and safety of some of these techniques have been well established, whereas for others, the oncological outcome data are only preliminary. The decision to use newer techniques should be directed by patient variables as well as the surgeon's training and competence with laparoscopy, robotics, or vaginal surgery.
    Mount Sinai Journal of Medicine A Journal of Translational and Personalized Medicine 12/2009; 76(6):567-76. · 1.99 Impact Factor