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Genomic Correlate of Exceptional Erlotinib Response in Head and Neck Squamous Cell Carcinoma [Case Report]
Van Allen, Eliezer M; Lui, Vivian W Y; Egloff, Ann Marie; Goetz, Eva M; Li, Hua; Johnson, Jonas T; Duvvuri, Umamaheswar; Bauman, Julie E; Stransky, Nicolas; Zeng, Yan; Gilbert, Breean R; Pendleton, Kelsey P; Wang, Lin; Chiosea, Simion; Sougnez, Carrie; Wagle, Nikhil; Zhang, Fan; Du, Yu; Close, David; Johnston, Paul A; McKenna, Aaron; Carter, Scott L; Golub, Todd R; Getz, Gad; Mills, Gordon B; Garraway, Levi A; Grandis, Jennifer R
IMPORTANCE/OBJECTIVE:Randomized clinical trials demonstrate no benefit for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in unselected patients with head and neck squamous cell carcinoma (HNSCC). However, a patient with stage IVA HNSCC received 13 days of neoadjuvant erlotinib and experienced a near-complete histologic response. OBJECTIVE:To determine a mechanism of exceptional response to erlotinib therapy in HNSCC. DESIGN, SETTING, AND PARTICIPANTS/METHODS:Single patient with locally advanced HNSCC who received erlotinib monotherapy in a window-of-opportunity clinical trial (patients scheduled to undergo primary cancer surgery are treated briefly with an investigational agent). Whole-exome sequencing of pretreatment tumor and germline patient samples was performed at a quaternary care academic medical center, and a candidate somatic variant was experimentally investigated for mediating erlotinib response. INTERVENTION/METHODS:A brief course of erlotinib monotherapy followed by surgical resection. MAIN OUTCOMES AND MEASURES/METHODS:Identification of pretreatment tumor somatic alterations that may contribute to the exceptional response to erlotinib. Hypotheses were formulated regarding enhanced erlotinib response in preclinical models harboring the patient tumor somatic variant MAPK1 E322K following the identification of tumor somatic variants. RESULTS:No EGFR alterations were observed in the pretreatment tumor DNA. Paradoxically, the tumor harbored an activating MAPK1 E322K mutation (allelic fraction 0.13), which predicts ERK activation and erlotinib resistance in EGFR-mutant lung cancer. The HNSCC cells with MAPK1 E322K exhibited enhanced EGFR phosphorylation and erlotinib sensitivity compared with wild-type MAPK1 cells. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:Selective erlotinib use in HNSCC may be informed by precision oncology approaches.
PMCID:4557203
PMID: 26181029
ISSN: 2374-2445
CID: 5481452
ANO1/TMEM16A interacts with EGFR and correlates with sensitivity to EGFR-targeting therapy in head and neck cancer
Bill, Anke; Gutierrez, Abraham; Kulkarni, Sucheta; Kemp, Carolyn; Bonenfant, Debora; Voshol, Hans; Duvvuri, Umamaheswar; Gaither, L Alex
The epidermal growth factor receptor (EGFR) contributes to the pathogenesis of head&neck squamous cell carcinoma (HNSCC). However, only a subset of HNSCC patients benefit from anti-EGFR targeted therapy. By performing an unbiased proteomics screen, we found that the calcium-activated chloride channel ANO1 interacts with EGFR and facilitates EGFR-signaling in HNSCC. Using structural mutants of EGFR and ANO1 we identified the trans/juxtamembrane domain of EGFR to be critical for the interaction with ANO1. Our results show that ANO1 and EGFR form a functional complex that jointly regulates HNSCC cell proliferation. Expression of ANO1 affected EGFR stability, while EGFR-signaling elevated ANO1 protein levels, establishing a functional and regulatory link between ANO1 and EGFR. Co-inhibition of EGFR and ANO1 had an additive effect on HNSCC cell proliferation, suggesting that co-targeting of ANO1 and EGFR could enhance the clinical potential of EGFR-targeted therapy in HNSCC and might circumvent the development of resistance to single agent therapy. HNSCC cell lines with amplification and high expression of ANO1 showed enhanced sensitivity to Gefitinib, suggesting ANO1 overexpression as a predictive marker for the response to EGFR-targeting agents in HNSCC therapy. Taken together, our results introduce ANO1 as a promising target and/or biomarker for EGFR-directed therapy in HNSCC.
PMCID:4496210
PMID: 25823819
ISSN: 1949-2553
CID: 5481392
Transoral robotic surgery for oropharyngeal squamous cell carcinoma
Schmitt, Nicole C; Duvvuri, Umamaheswar
PURPOSE OF REVIEW/OBJECTIVE:This article reviews recent information on outcomes, indications, techniques, and cost of transoral robotic surgery (TORS) for oropharyngeal squamous cell carcinoma (OPSCC). New information on comparisons between TORS, conventional surgery techniques, and chemoradiation is also highlighted. RECENT FINDINGS/RESULTS:Consistent with prior reports, recent studies show excellent oncologic and functional outcomes with TORS for OPSCC. As surgeon experience with this relatively new technique has increased, outcomes continue to improve and complications are rare. TORS may also have a role in management of carcinoma of unknown primary site. Compared with other treatment modalities, TORS for OPSCC may result in similar oncologic outcomes, improved functional outcomes, and decreased cost. SUMMARY/CONCLUSIONS:TORS for OPSCC results in excellent functional and oncologic outcomes. Randomized clinical trials are needed to compare TORS with adjuvant therapy to definitive chemoradiation and will determine whether adjuvant therapy and associated morbidity can be decreased without compromising survival.
PMID: 25692632
ISSN: 1531-6998
CID: 5481382
A prospective phase 2 trial of reirradiation with stereotactic body radiation therapy plus cetuximab in patients with previously irradiated recurrent squamous cell carcinoma of the head and neck
Vargo, John A; Ferris, Robert L; Ohr, James; Clump, David A; Davis, Kara S; Duvvuri, Umamaheswar; Kim, Seungwon; Johnson, Jonas T; Bauman, Julie E; Gibson, Michael K; Branstetter, Barton F; Heron, Dwight E
PURPOSE/OBJECTIVE:Salvage options for unresectable locally recurrent, previously irradiated squamous cell carcinoma of the head and neck (rSCCHN) are limited. Although the addition of reirradiation may improve outcomes compared to chemotherapy alone, significant toxicities limit salvage reirradiation strategies, leading to suboptimal outcomes. We therefore designed a phase 2 protocol to evaluate the efficacy of stereotactic body radiation therapy (SBRT) plus cetuximab for rSCCHN. METHODS AND MATERIALS/METHODS:From July 2007 to March 2013, 50 patients >18 years of age with inoperable locoregionally confined rSCCHN within a previously irradiated field receiving ≥60 Gy, with a Zubrod performance status of 0 to 2, and normal hepatic and renal function were enrolled. Patients received concurrent cetuximab (400 mg/m(2) on day -7 and then 250 mg/m(2) on days 0 and +8) plus SBRT (40-44 Gy in 5 fractions on alternating days over 1-2 weeks). Primary endpoints were 1-year locoregional progression-free survival and National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 graded toxicity. RESULTS:Median follow-up for surviving patients was 18 months (range: 10-70). The 1-year local PFS rate was 60% (95% confidence interval [CI]: 44%-75%), locoregional PFS was 37% (95% CI: 23%-53%), distant PFS was 71% (95% CI: 54%-85%), and PFS was 33% (95% CI: 20%-49%). The median overall survival was 10 months (95% CI: 7-16), with a 1-year overall survival of 40% (95% CI: 26%-54%). At last follow-up, 69% died of disease, 4% died with disease, 15% died without progression, 10% were alive without progression, and 2% were alive with progression. Acute and late grade 3 toxicity was observed in 6% of patients respectively. CONCLUSIONS:SBRT with concurrent cetuximab appears to be a safe salvage treatment for rSCCHN of short overall treatment time.
PMID: 25680594
ISSN: 1879-355x
CID: 5481362
A single-port operator-controlled flexible endoscope system for endoscopic skull base surgery
Schuler, P J; Scheithauer, M; Rotter, N; Veit, J; Duvvuri, U; Hoffmann, T K
OBJECTIVE:In a human cadaver study, a single-port operator-controlled flexible endoscope (Flex® System), facilitated with a high-definition camera and two accessory channels was tested for skull base surgery. DESIGN/METHODS:Skull base surgery was performed on human cadavers (n=4) using the Flex® System. A modified surgical midfacial approach, performed by rigid standard tools, was used for access to the sinus system, the skull base, and the middle cranial fossa. RESULTS:Endoscopic skull base visualization with the Flex® System is feasible. Surgical procedures performed included extended sinus surgery, anterior skull base approach, and visualization of the brain stem in the posterior cranial fossa. Important landmarks of the anterior skull base were visualized and manipulated by flexible compatible tools. CONCLUSION/CONCLUSIONS:The Flex® System allows for manipulation of the anterior skull base and visualization of the posterior cranial fossa in a preclinical setting. Further studies as well as development of supplemental tools are in progress.
PMID: 25689971
ISSN: 1433-0458
CID: 5487972
Transoral surgery for oropharyngeal tumors using the Medrobotics(®) Flex(®) System - a case report
Mandapathil, Magis; Duvvuri, Umamaheswar; Güldner, Christian; Teymoortash, Afshin; Lawson, George; Werner, Jochen A
INTRODUCTION/BACKGROUND:Transoral resection of pharyngeal tumors with acceptable oncological and functional results can be challenging due to their location in a narrow anatomic space. CASE PRESENTATION/METHODS:In this case report, we demonstrate successful visualization and resection of a squamous cell carcinoma of the oropharynx using the novel Medrobotics(®) Flex(®) System. The Medrobotics(®) Flex(®) System (Medrobotics Corp., Raynham, MA, USA) is an operator controlled flexible endoscope system that includes a rigid endoscope and computer-assisted controllers, with two external channels for the use of compatible, 3.5mm flexible instruments. DISCUSSION/CONCLUSIONS:In a 74-year old female patient a T1 squamous cell carcinoma of the oropharynx was visualized and completely resected using this system. The Medrobotics(®) Flex(®) System is a promising device for transoral approaches in resection of tumors within the pharynx. CONCLUSION/CONCLUSIONS:Good visualization, access, and flexibility of the endoscope and instruments are hereby clear advantages of the system compared to commonly used systems.
PMCID:4430123
PMID: 25853845
ISSN: 2210-2612
CID: 5481412
Phase I study of cetuximab, intensity-modulated radiotherapy (C-IMRT), and intratumoral EGFR antisense (AS) DNA in patients with locally advanced head and neck cancer (HNC) [Meeting Abstract]
Bauman, Julie E.; Duvvuri, Umamaheswar; Gooding, William E.; Clump, David Andrew; Karlovits, Brian J.; Wehbe, Ahmad Mouhamad; Miller, Frank R.; Johnson, Jonas Talmadge; Ferris, Robert L.; Kim, Seungwon; Heron, Dwight Earl; Ohr, James; Grandis, Jennifer R.; Argiris, Athanassios
ISI:000358036901391
ISSN: 0732-183x
CID: 5482562
Outcomes for Carotid Blowout Interventions in Patients With Head and Neck Cancer [Meeting Abstract]
Liang, Nathan L.; Guedes, Brian D.; Duvvuri, Umamaheswar; Singh, Michael J.; Chaer, Rabih A.; Makaroun, Michel S.; Sachdev, Ulka
ISI:000360357500066
ISSN: 0741-5214
CID: 5482592
HER3 inhibition potentiates anti-tumor effects of PI3K inhibitors in pre-clinical models of HNSCC [Meeting Abstract]
Davis, Kara S.; Khan, Nayel; Kemp, Carolyn; Kulkarni, Sucheta; Alvarado, Diego; LaVallee, Theresa; Grandis, Jennifer R.; Duvvuri, Umamaheswar
ISI:000371578503164
ISSN: 0008-5472
CID: 5482602
Influence of chloride flux on cell motility in head and neck squamous cell carcinoma [Meeting Abstract]
Khan, Nayel; Steehler, Kevin; Kemp, Carolyn; Kulkarni, Sucheta; Davis, Kara; Duvvuri, Umamaheswar
ISI:000371597105284
ISSN: 0008-5472
CID: 5482612