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2. TAM family receptors in conjunction with MAPK signalling are involved in acquired resistance to PI3Kα inhibition in head and neck squamous cell carcinoma

Author

Ruicci, Kara M, Meens, Jalna, Plantinga, Paul, Stecho, William, Pinto, Nicole, Yoo, John, Fung, Kevin, MacNeil, Danielle, Mymryk, Joe S, Barrett, John W, Howlett, Christopher J, Boutros, Paul C, Ailles, Laurie, and Nichols, Anthony C

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Rare Diseases, Dental/Oral and Craniofacial Disease, Biotechnology, Cancer, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Animals, Apoptosis, Biomarkers, Tumor, Cell Movement, Cell Proliferation, Class I Phosphatidylinositol 3-Kinases, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Head and Neck Neoplasms, Humans, MAP Kinase Signaling System, Mice, Prognosis, Proto-Oncogene Proteins, Receptor Protein-Tyrosine Kinases, Squamous Cell Carcinoma of Head and Neck, Survival Rate, Thiazoles, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Axl Receptor Tyrosine Kinase, Alpelisib, BYL719, PI3-kinase, PI3K, Head and neck cancer, HNSCC, AXL, TYRO3, Oncology and carcinogenesis
Abstract

BackgroundAberrant activation of the phosphatidylinositol 3-kinase (PI3K) pathway is common in many malignancies, including head and neck squamous cell carcinoma (HNSCC). Despite pre-clinical and clinical studies, outcomes from targeting the PI3K pathway have been underwhelming and the development of drug resistance poses a significant barrier to patient treatment. In the present study, we examined mechanisms of acquired resistance to the PI3Kα inhibitor alpelisib (formerly BYL719) in HNSCC cell lines and patient-derived xenografts (PDXs).MethodsFive unique PDX mouse models and three HNSCC cell lines were used. All cell lines and xenografts underwent genomic characterization prior to study. Serial drug treatment was conducted in vitro and in vivo to develop multiple, clinically-significant models of resistance to alpelisib. We then used reverse phase protein arrays (RPPAs) to profile the expression of proteins in parental and drug-resistant models. Top hits were validated by immunoblotting and immunohistochemistry. Flow cytometric analysis and RNA interference studies were then used to interrogate the molecular mechanisms underlying acquired drug resistance.ResultsProlonged treatment with alpelisib led to upregulation of TAM family receptor tyrosine kinases TYRO3 and AXL. Importantly, a significant shift in expression of both TYRO3 and AXL to the cell surface was detected in drug-resistant cells. Targeted knockdown of TYRO3 and AXL effectively re-sensitized resistant cells to PI3Kα inhibition. In vivo, resistance to alpelisib emerged following 20-35 days of treatment in all five PDX models. Elevated TYRO3 expression was detected in drug-resistant PDX tissues. Downstream of TYRO3 and AXL, we identified activation of intracellular MAPK signalling. Inhibition of MAPK signalling also re-sensitized drug-resistant cells to alpelisib.ConclusionsWe have identified TYRO3 and AXL receptors to be key mediators of resistance to alpelisib, both in vitro and in vivo. Our findings suggest that pan-TAM inhibition is a promising avenue for combinatorial or second-line therapy alongside PI3Kα inhibition. These findings advance our understanding of the role TAM receptors play in modulating the response of HNSCC to PI3Kα inhibition and suggest a means to prevent, or at least delay, resistance to PI3Kα inhibition in order to improve outcomes for HNSCC patients.

Published
2020

3. Flavopiridol causes cell cycle inhibition and demonstrates anti-cancer activity in anaplastic thyroid cancer models

Author

Pinto, Nicole, Prokopec, Stephenie D, Ghasemi, Farhad, Meens, Jalna, Ruicci, Kara M, Khan, Imran M, Mundi, Neil, Patel, Krupal, Han, Myung W, Yoo, John, Fung, Kevin, MacNeil, Danielle, Mymryk, Joe S, Datti, Alessandro, Barrett, John W, Boutros, Paul C, Ailles, Laurie, and Nichols, Anthony C

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Cancer, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Animals, Apoptosis, Cell Cycle Checkpoints, Cell Line, Tumor, Cell Movement, Cell Proliferation, Cyclin-Dependent Kinase 9, Flavonoids, Humans, Male, Mice, Mice, Inbred NOD, Mice, SCID, Piperidines, Protein Kinase Inhibitors, RNA Interference, RNA, Small Interfering, Thyroid Carcinoma, Anaplastic, Thyroid Neoplasms, Transplantation, Heterologous, General Science & Technology
Abstract

Anaplastic thyroid cancer (ATC) is a rare, but nearly uniformly fatal disease that is typically resistant to chemotherapy and radiation. Alternative strategies to target this cancer at a molecular level are necessary in order to improve dismal outcomes for ATC patients. We examined the effects of flavopiridol, a CDK inhibitor, in a panel of ATC cell lines. When cell lines were treated over a ten-point concentration range, CAL62, KMH2 and BHT-101 cell lines had a sub micromolar half-maximal inhibitory concentration, while no effect was seen in the non-cancerous cell line IMR-90. Flavopiridol treatment resulted in decreased levels of the cell cycle proteins CDK9 and MCL1, and induced cell cycle arrest. Flavopiridol also decreased the in vitro ability of ATC cells to form colonies and impeded migration using a transwell migration assay. In vivo, flavopiridol decreased tumor weight and tumor volume over time in a patient-derived xenograft model of ATC. Given the observed in vitro and in vivo activity, flavopiridol warrants further investigation for treatment of ATC.

Published
2020

4. Spleen tyrosine kinase expression is correlated with human papillomavirus in head and neck cancer

Author

Black, Morgan, Ghasemi, Farhad, Sun, Ren X., Stecho, William, Datti, Alessandro, Meens, Jalna, Pinto, Nicole, Ruicci, Kara M., Khan, M. Imran, Han, Myung Woul, Shaikh, Mushfiq, Yoo, John, Fung, Kevin, MacNeil, Danielle, Palma, David A., Winquist, Eric, Howlett, Christopher J., Mymryk, Joe S., Ailles, Laurie, Boutros, Paul C., Barrett, John W., and Nichols, Anthony C.

Published
2020
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14. Supplementary Figure 6 from PI3K Inhibitors Curtail MYC-Dependent Mutant p53 Gain-of-Function in Head and Neck Squamous Cell Carcinoma

Author

Ganci, Federica, primary, Pulito, Claudio, primary, Valsoni, Sara, primary, Sacconi, Andrea, primary, Turco, Chiara, primary, Vahabi, Mahrou, primary, Manciocco, Valentina, primary, Mazza, Emilia Maria Cristina, primary, Meens, Jalna, primary, Karamboulas, Christina, primary, Nichols, Anthony C., primary, Covello, Renato, primary, Pellini, Raul, primary, Spriano, Giuseppe, primary, Sanguineti, Giuseppe, primary, Muti, Paola, primary, Bicciato, Silvio, primary, Ailles, Laurie, primary, Strano, Sabrina, primary, Fontemaggi, Giulia, primary, and Blandino, Giovanni, primary

Published
2023
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15. Supplementary Figure 3 from PI3K Inhibitors Curtail MYC-Dependent Mutant p53 Gain-of-Function in Head and Neck Squamous Cell Carcinoma

Author

Ganci, Federica, primary, Pulito, Claudio, primary, Valsoni, Sara, primary, Sacconi, Andrea, primary, Turco, Chiara, primary, Vahabi, Mahrou, primary, Manciocco, Valentina, primary, Mazza, Emilia Maria Cristina, primary, Meens, Jalna, primary, Karamboulas, Christina, primary, Nichols, Anthony C., primary, Covello, Renato, primary, Pellini, Raul, primary, Spriano, Giuseppe, primary, Sanguineti, Giuseppe, primary, Muti, Paola, primary, Bicciato, Silvio, primary, Ailles, Laurie, primary, Strano, Sabrina, primary, Fontemaggi, Giulia, primary, and Blandino, Giovanni, primary

Published
2023
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16. Supplementary Figure 7 from PI3K Inhibitors Curtail MYC-Dependent Mutant p53 Gain-of-Function in Head and Neck Squamous Cell Carcinoma

Author

Ganci, Federica, primary, Pulito, Claudio, primary, Valsoni, Sara, primary, Sacconi, Andrea, primary, Turco, Chiara, primary, Vahabi, Mahrou, primary, Manciocco, Valentina, primary, Mazza, Emilia Maria Cristina, primary, Meens, Jalna, primary, Karamboulas, Christina, primary, Nichols, Anthony C., primary, Covello, Renato, primary, Pellini, Raul, primary, Spriano, Giuseppe, primary, Sanguineti, Giuseppe, primary, Muti, Paola, primary, Bicciato, Silvio, primary, Ailles, Laurie, primary, Strano, Sabrina, primary, Fontemaggi, Giulia, primary, and Blandino, Giovanni, primary

Published
2023
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17. Supplementary Figure 4 from PI3K Inhibitors Curtail MYC-Dependent Mutant p53 Gain-of-Function in Head and Neck Squamous Cell Carcinoma

Author

Ganci, Federica, primary, Pulito, Claudio, primary, Valsoni, Sara, primary, Sacconi, Andrea, primary, Turco, Chiara, primary, Vahabi, Mahrou, primary, Manciocco, Valentina, primary, Mazza, Emilia Maria Cristina, primary, Meens, Jalna, primary, Karamboulas, Christina, primary, Nichols, Anthony C., primary, Covello, Renato, primary, Pellini, Raul, primary, Spriano, Giuseppe, primary, Sanguineti, Giuseppe, primary, Muti, Paola, primary, Bicciato, Silvio, primary, Ailles, Laurie, primary, Strano, Sabrina, primary, Fontemaggi, Giulia, primary, and Blandino, Giovanni, primary

Published
2023
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18. Supplementary Data from PI3K Inhibitors Curtail MYC-Dependent Mutant p53 Gain-of-Function in Head and Neck Squamous Cell Carcinoma

Author

Ganci, Federica, primary, Pulito, Claudio, primary, Valsoni, Sara, primary, Sacconi, Andrea, primary, Turco, Chiara, primary, Vahabi, Mahrou, primary, Manciocco, Valentina, primary, Mazza, Emilia Maria Cristina, primary, Meens, Jalna, primary, Karamboulas, Christina, primary, Nichols, Anthony C., primary, Covello, Renato, primary, Pellini, Raul, primary, Spriano, Giuseppe, primary, Sanguineti, Giuseppe, primary, Muti, Paola, primary, Bicciato, Silvio, primary, Ailles, Laurie, primary, Strano, Sabrina, primary, Fontemaggi, Giulia, primary, and Blandino, Giovanni, primary

Published
2023
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19. Supplementary Figure 1 from PI3K Inhibitors Curtail MYC-Dependent Mutant p53 Gain-of-Function in Head and Neck Squamous Cell Carcinoma

Author

Ganci, Federica, primary, Pulito, Claudio, primary, Valsoni, Sara, primary, Sacconi, Andrea, primary, Turco, Chiara, primary, Vahabi, Mahrou, primary, Manciocco, Valentina, primary, Mazza, Emilia Maria Cristina, primary, Meens, Jalna, primary, Karamboulas, Christina, primary, Nichols, Anthony C., primary, Covello, Renato, primary, Pellini, Raul, primary, Spriano, Giuseppe, primary, Sanguineti, Giuseppe, primary, Muti, Paola, primary, Bicciato, Silvio, primary, Ailles, Laurie, primary, Strano, Sabrina, primary, Fontemaggi, Giulia, primary, and Blandino, Giovanni, primary

Published
2023
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20. Supplementary Figure 2 from PI3K Inhibitors Curtail MYC-Dependent Mutant p53 Gain-of-Function in Head and Neck Squamous Cell Carcinoma

Author

Ganci, Federica, primary, Pulito, Claudio, primary, Valsoni, Sara, primary, Sacconi, Andrea, primary, Turco, Chiara, primary, Vahabi, Mahrou, primary, Manciocco, Valentina, primary, Mazza, Emilia Maria Cristina, primary, Meens, Jalna, primary, Karamboulas, Christina, primary, Nichols, Anthony C., primary, Covello, Renato, primary, Pellini, Raul, primary, Spriano, Giuseppe, primary, Sanguineti, Giuseppe, primary, Muti, Paola, primary, Bicciato, Silvio, primary, Ailles, Laurie, primary, Strano, Sabrina, primary, Fontemaggi, Giulia, primary, and Blandino, Giovanni, primary

Published
2023
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21. Supplementary Figure 5 from PI3K Inhibitors Curtail MYC-Dependent Mutant p53 Gain-of-Function in Head and Neck Squamous Cell Carcinoma

Author

Ganci, Federica, primary, Pulito, Claudio, primary, Valsoni, Sara, primary, Sacconi, Andrea, primary, Turco, Chiara, primary, Vahabi, Mahrou, primary, Manciocco, Valentina, primary, Mazza, Emilia Maria Cristina, primary, Meens, Jalna, primary, Karamboulas, Christina, primary, Nichols, Anthony C., primary, Covello, Renato, primary, Pellini, Raul, primary, Spriano, Giuseppe, primary, Sanguineti, Giuseppe, primary, Muti, Paola, primary, Bicciato, Silvio, primary, Ailles, Laurie, primary, Strano, Sabrina, primary, Fontemaggi, Giulia, primary, and Blandino, Giovanni, primary

Published
2023
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30. Role of microRNA-dependent PTEN downregulation in the resistance to PI3K inhibitor alpelisib in head & neck squamous cell carcinoma

Author

Pulito, Claudio, primary, Ganci, Federica, additional, Frascolla, Carlotta, additional, Sacconi, Andrea, additional, Benedetti, Anna, additional, Manciocco, Valentina, additional, Covello, Renato, additional, Morrone, Aldo, additional, Pellini, Raul, additional, Muti, Paola, additional, Meens, Jalna, additional, Karamboulas, Christina, additional, Nichols, Anthony, additional, Ailles, Laurie, additional, FAZI, FRANCESCO, additional, Strano, Sabrina, additional, Fontemaggi, Giulia, additional, and Blandino, Giovanni, additional

Published
2023
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31. Development and Validation of an Oral Cavity Cancer Outcomes Prediction Score Incorporating Patient-Derived Xenograft Engraftment

Author

Id Said, Badr, primary, Ailles, Laurie, additional, Karamboulas, Christina, additional, Meens, Jalna, additional, Huang, Shao Hui, additional, Xu, Wei, additional, Keshavarzi, Sareh, additional, Bratman, Scott V., additional, Cho, B. C. John, additional, Giuliani, Meredith, additional, Hahn, Ezra, additional, Kim, John, additional, O’Sullivan, Brian, additional, Ringash, Jolie, additional, Waldron, John, additional, Spreafico, Anna, additional, de Almeida, John R., additional, Chepeha, Douglas B., additional, Irish, Jonathan C., additional, Goldstein, David P., additional, Hope, Andrew, additional, and Hosni, Ali, additional

Published
2022
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34. 45: Patient-Derived Xenograft Engraftment Predicts Oral Cavity Cancer Outcomes

Author

Said, Badr Id, primary, Laurie, Ailles, additional, Karamboulas, Christina, additional, Meens, Jalna, additional, Huang, Shao Hui, additional, Xu, Wei, additional, Keshavarzi, Sareh, additional, Bratman, Scott V., additional, Cho, B.C. John, additional, Giuliani, Meredith, additional, Hahn, Ezra, additional, Kim, John, additional, O’Sullivan, Brian, additional, Ringash, Jolie, additional, Waldron, John, additional, Spreafico, Anna, additional, de Almeida, John R., additional, Chepeha, Douglas B., additional, Irish, Jonathan C., additional, Goldstein, David P., additional, Hope, Andrew, additional, and Hosni, Ali, additional

Published
2021
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35. Additional file 1 of Dose predictions for [177Lu]Lu-DOTA-panitumumab F(ab′)2 in NRG mice with HNSCC patient-derived tumour xenografts based on [64Cu]Cu-DOTA-panitumumab F(ab′)2 – implications for a PET theranostic strategy

Author

Ku, Anthony, Kondo, Misaki, Cai, Zhongli, Meens, Jalna, Li, Min Rong, Ailles, Laurie, and Reilly, Raymond M.

Subjects
neoplasms
Abstract

Fig. S1. SDS PAGE analysis of trastuzumab IgG and F(ab′)2 under non-reducing (lanes 1, 2, respectively) or reducing (lanes 3, 4, respectively) conditions on a 7.5% Tris/Glycine mini-gel stained with Coomassie blue. Table S1. Estimated radiation equivalent doses in a tumour-bearing NRG mouse for [64Cu]Cu-DOTA-panitumumab F(ab´)2. Table S2. Projected radiation equivalent doses for a female human adult with a 2 cm tumour in the neck for [64Cu]Cu-DOTA-panitumumab F(ab´)2 or [177Lu]Lu-DOTA-panitumumab F(ab´)2. (DOCX 244 kb)

Published
2021
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37. PI3K Inhibitors Curtail MYC-Dependent Mutant p53 Gain-of-Function in Head and Neck Squamous Cell Carcinoma

Author

Ganci, Federica, primary, Pulito, Claudio, additional, Valsoni, Sara, additional, Sacconi, Andrea, additional, Turco, Chiara, additional, Vahabi, Mahrou, additional, Manciocco, Valentina, additional, Mazza, Emilia Maria Cristina, additional, Meens, Jalna, additional, Karamboulas, Christina, additional, Nichols, Anthony C., additional, Covello, Renato, additional, Pellini, Raul, additional, Spriano, Giuseppe, additional, Sanguineti, Giuseppe, additional, Muti, Paola, additional, Bicciato, Silvio, additional, Ailles, Laurie, additional, Strano, Sabrina, additional, Fontemaggi, Giulia, additional, and Blandino, Giovanni, additional

Published
2020
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39. Distinct fibroblast functional states drive clinical outcomes in ovarian cancer and are regulated by TCF21

Author

Hussain, Ali, primary, Voisin, Veronique, primary, Poon, Stephanie, primary, Karamboulas, Christina, primary, Bui, Ngoc Hoang Bao, primary, Meens, Jalna, primary, Dmytryshyn, Julia, primary, Ho, Victor W., primary, Tang, Kwan Ho, primary, Paterson, Joshua, primary, Clarke, Blaise A., primary, Bernardini, Marcus Q., primary, Bader, Gary D., primary, Neel, Benjamin G., primary, and Ailles, Laurie E., primary

Published
2020
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41. Dose predictions for [177Lu]Lu-DOTA-panitumumab F(ab′)2 in NRG mice with HNSCC patient-derived tumour xenografts based on [64Cu]Cu-DOTA-panitumumab F(ab′)2 – implications for a PET theranostic strategy

Author

Ku, Anthony, Kondo, Misaki, Cai, Zhongli, Meens, Jalna, Li, Min Rong, Ailles, Laurie, and Reilly, Raymond M.

Subjects
EPIDERMAL growth factor receptors, POSITRON emission tomography, COMPUTED tomography, RADIOCHEMICAL purification, XENOGRAFTS
Abstract

Background: Epidermal growth factor receptors (EGFR) are overexpressed on many head and neck squamous cell carcinoma (HNSCC). Radioimmunotherapy (RIT) with F(ab')2 of the anti-EGFR monoclonal antibody panitumumab labeled with the β-particle emitter, 177Lu may be a promising treatment for HNSCC. Our aim was to assess the feasibility of a theranostic strategy that combines positron emission tomography (PET) with [64Cu]Cu-DOTA-panitumumab F(ab')2 to image HNSCC and predict the radiation equivalent doses to the tumour and normal organs from RIT with [177Lu]Lu-DOTA-panitumumab F(ab')2. Results: Panitumumab F(ab')2 were conjugated to DOTA and complexed to 64Cu or 177Lu in high radiochemical purity (95.6 ± 2.1% and 96.7 ± 3.5%, respectively) and exhibited high affinity EGFR binding (Kd = 2.9 ± 0.7 × 10− 9 mol/L). Biodistribution (BOD) studies at 6, 24 or 48 h post-injection (p.i.) of [64Cu]Cu-DOTA-panitumumab F(ab')2 (5.5–14.0 MBq; 50 μg) or [177Lu]Lu-DOTA-panitumumab F(ab')2 (6.5 MBq; 50 μg) in NRG mice with s.c. HNSCC patient-derived xenografts (PDX) overall showed no significant differences in tumour uptake but modest differences in normal organ uptake were noted at certain time points. Tumours were imaged by microPET/CT with [64Cu]Cu-DOTA-panitumumab F(ab')2 or microSPECT/CT with [177Lu]Lu-DOTA-panitumumab F(ab')2 but not with irrelevant [177Lu]Lu-DOTA-trastuzumab F(ab')2. Tumour uptake at 24 h p.i. of [64Cu]Cu-DOTA-panitumumab F(ab')2 [14.9 ± 1.1% injected dose/gram (%ID/g) and [177Lu]Lu-DOTA-panitumumab F(ab')2 (18.0 ± 0.4%ID/g) were significantly higher (P < 0.05) than [177Lu]Lu-DOTA-trastuzumab F(ab')2 (2.6 ± 0.5%ID/g), demonstrating EGFR-mediated tumour uptake. There were no significant differences in the radiation equivalent doses in the tumour and most normal organs estimated for [177Lu]Lu-DOTA-panitumumab F(ab')2 based on the BOD of [64Cu]Cu-DOTA-panitumumab F(ab')2 compared to those estimated directly from the BOD of [177Lu]Lu-DOTA-panitumumab F(ab')2 except for the liver and whole body which were modestly underestimated by [64Cu]Cu-DOTA-panitumumab F(ab')2. Region-of-interest (ROI) analysis of microPET/CT images provided dose estimates for the tumour and liver that were not significantly different for the two radioimmunoconjugates. Human doses from administration of [177Lu]Lu-DOTA-panitumumab F(ab')2 predicted that a 2 cm diameter HNSCC tumour in a patient would receive 1.1–1.5 mSv/MBq and the whole body dose would be 0.15–0.22 mSv/MBq. Conclusion: A PET theranostic strategy combining [64Cu]Cu-DOTA-panitumumab F(ab')2 to image HNSCC tumours and predict the equivalent radiation doses in the tumour and normal organs from RIT with [177Lu]Lu-DOTA-panitumumab F(ab')2 is feasible. RIT with [177Lu]Lu-DOTA-panitumumab F(ab')2 may be a promising approach to treatment of HNSCC due to frequent overexpression of EGFR. [ABSTRACT FROM AUTHOR]

Published
2021
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43. Molecular and functional heterogeneity of cancer associated fibroblasts in high-grade serous ovarian cancer

Author

Hussain, Ali, primary, Voisin, Veronique, additional, Poon, Stephanie, additional, Dmytryshyn, Julia, additional, Richman, Cory, additional, Meens, Jalna, additional, Ho, Victor W, additional, Tang, Kwan Ho, additional, Paterson, Joshua, additional, Clarke, Blaise, additional, Bernardini, Marcus Q, additional, Bader, Gary D, additional, Neel, Benjamin G, additional, and Ailles, Laurie E, additional

Published
2019
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44. A controlled trial of HNSCC patient‐derived xenografts reveals broad efficacy of PI3Kα inhibition in controlling tumor growth

Author

Ruicci, Kara M., primary, Meens, Jalna, additional, Sun, Ren X., additional, Rizzo, Giananthony, additional, Pinto, Nicole, additional, Yoo, John, additional, Fung, Kevin, additional, MacNeil, Danielle, additional, Mymryk, Joe S., additional, Barrett, John W., additional, Boutros, Paul C., additional, Ailles, Laurie, additional, and Nichols, Anthony C., additional

Published
2018
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45. Patient-Derived Xenografts for Prognostication and Personalized Treatment for Head and Neck Squamous Cell Carcinoma

Author

Karamboulas, Christina, primary, Bruce, Jeffrey P., additional, Hope, Andrew J., additional, Meens, Jalna, additional, Huang, Shao Hui, additional, Erdmann, Natalie, additional, Hyatt, Elzbieta, additional, Pereira, Keira, additional, Goldstein, David P., additional, Weinreb, Ilan, additional, Su, Jie, additional, O’Sullivan, Brian, additional, Tiedemann, Rodger, additional, Liu, Fei-Fei, additional, Pugh, Trevor J., additional, Bratman, Scott V., additional, Xu, Wei, additional, and Ailles, Laurie, additional

Published
2018
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48. Rapid determination of the tumour stroma ratio in squamous cell carcinomas with desorption electrospray ionization mass spectrometry (DESI-MS): a proof-of-concept demonstration

Author

Woolman, Michael, primary, Tata, Alessandra, additional, Dara, Delaram, additional, Meens, Jalna, additional, D'Arcangelo, Elisa, additional, Perez, Consuelo J., additional, Saiyara Prova, Shamina, additional, Bluemke, Emma, additional, Ginsberg, Howard J., additional, Ifa, Demian, additional, McGuigan, Alison, additional, Ailles, Laurie, additional, and Zarrine-Afsar, Arash, additional

Published
2017
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49. Correction: Rapid determination of the tumour stroma ratio in squamous cell carcinomas with desorption electrospray ionization mass spectrometry (DESI-MS): a proof-of-concept demonstration

Author

Woolman, Michael, primary, Tata, Alessandra, additional, Dara, Delaram, additional, Meens, Jalna, additional, D'Arcangelo, Elisa, additional, Perez, Consuelo J., additional, Prova, Shamina Saiyara, additional, Bluemke, Emma, additional, Ginsberg, Howard J., additional, Ifa, Demian, additional, McGuigan, Alison, additional, Ailles, Laurie, additional, and Zarrine-Afsar, Arash, additional

Published
2017
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50. A controlled trial of HNSCC patient‐derived xenografts reveals broad efficacy of PI3Kα inhibition in controlling tumor growth.

Author

Ruicci, Kara M., Meens, Jalna, Sun, Ren X., Rizzo, Giananthony, Pinto, Nicole, Yoo, John, Fung, Kevin, MacNeil, Danielle, Mymryk, Joe S., Barrett, John W., Boutros, Paul C., Ailles, Laurie, and Nichols, Anthony C.

Subjects
TUMOR growth, XENOGRAFTS, SQUAMOUS cell carcinoma, CLINICAL trials, PHOSPHATIDYLINOSITOL 3-kinases
Abstract

Head and neck squamous cell carcinomas (HNSCCs) frequently harbor alterations in the PI3K/AKT/mTOR signaling axis, particularly in the PIK3CA gene. PI3K‐targeted agents have therefore gained considerable preclinical and clinical interest as emerging therapies for HNSCC. Identification of predictive biomarkers of response would advance the clinical application of PI3K‐targeted drugs for patients, in order to achieve maximal benefit. To date, studies of drug biomarkers have largely focused on screening cell lines, with much more limited in vivo testing, usually only as validation. This approach has rarely enabled accurate predictions of clinical efficacy. Recently, clinical trials of PDX models (PDX clinical trials) have been introduced as a preclinical approach to interrogate interpatient response heterogeneity. Already, PDX clinical trial responses have been demonstrated to correlate closely with patient outcomes. Here, using both an HNSCC specific, 28‐cell line panel and a PDX clinical trial of 80 xenografts derived from 20 unique HNSCC tumors, we systematically examine patterns of response to PI3K inhibition in HNSCC. We find EGFR, AKT1 and CSMD1 copy number aberrations, but not PIK3CA mutations, to be associated with responsiveness to PI3K‐targeted drugs. Further, we reveal PI3Kα inhibition to be almost globally tumoristatic in HNSCC xenografts regardless of PIK3CA mutational status, emphasizing its potential as a stabilizing neoadjuvant therapy for HNSCC patients. What's new? To date, profiling of anti‐cancer therapeutics in head and neck squamous cell carcinoma (HNSCC) cell lines has rarely resulted in accurate predictions of clinical efficacy. Using patient‐derived xenograft (PDX) models, which more closely replicate both intra‐ and inter‐tumor heterogeneity, targeted therapeutics can be interrogated in a more clinically‐relevant model. Here, the authors conducted a Phase II‐like trial of genomically‐characterized HNSCC PDXs to examine PI3‐kinase targeting and identified a role for PI3‐kinase inhibition in the neoadjuvant setting. [ABSTRACT FROM AUTHOR]

Published
2019
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