Boucher, Yves, PhD

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Delivery of Oncolytic Viruses and Large Therapeutic Agents in Tumors

The therapeutic success of oncolytic viruses and other nanotherapeutics is severely limited by their poor diffusion and distribution through the tumor interstitial space. We have shown that collagen fibers in the tumor interstitial matrix hinder the diffusion of large molecules, and the penetration of viral particles. We used relaxin – a small hormone which stimulates the secretion of matrix metalloproteinases and inhibits collagen synthesis – to improve the diffusion of large molecules in collagen-rich tumors. Multiphoton laser scanning microscopy (MPLSM) and second harmonic generation (SHG) imaging of collagen fibers in living tumors demonstrated that relaxin enhances collagen degradation. We also found that bacterial collagenase or mammalian collagenases – matrix metallo-proteinase-1 or -8 – can improve the intratumoral penetration and anti-tumor efficacy of oncolytic viruses. We recently tested if losartan – a clinically approved angiotensin II receptor blocker (ARB) with noted anti-fibrotic activity – can enhance the penetration and efficacy of nanomedicine. We found that losartan led to a dose-dependent reduction in stromal collagen in several tumor models in mice. Furthermore, losartan improved vascular perfusion, the distribution and therapeutic effectiveness of oncolytic viruses, Doxil and small cytotoxic agents. Based on our experimental results with losartan, we initiated a clinical trial at Massachusetts General Hospital that will determine in patients with pancreatic cancer if losartan improves the effectiveness of small cytotoxic agents.

The narrow spacing between cancer cells is also a major barrier hindering the movement of oncolytic viruses and other nanotherapeutics. To bypass the cellular barrier, we tested the hypothesis that void spaces produced by cancer cell apoptosis improve the initial spread of oncolytic virus. In mice with mammary tumors, cancer cell apoptosis – induced by doxycycline-regulated expression/activation of caspase-8 or cytotoxic agents – enhanced the viral spread and therapeutic effectiveness of oncolytic virus injected intratumorally. In order to improve the systemic efficacy of nanotherapeutics targeted both at primary and metastatic tumors, it is also essential to identify agents that will improve the vascular extravasation of large therapeutics injected intravenously. We are testing if targeting tumor blood vessels, cancer cells, or both improves the delivery and effectiveness of nanotherapeutics.

Tumor Cell Migration and Metastasis

We are studying how the genetic modulation of matrix metalloproteinases or transcription factors affects cancer cell migration, fibrillar collagen and vascular basement membrane remodeling, lymph and blood vessel invasion, and lymph node and distant metastasis. We use MPLSM and tumors in transparent mammary windows to assess tumor cell migration phenotypes (e.g. amoeboid, mesenchymal) and velocity, and SHG imaging to visualize the interaction of cancer or stromal cells with collagen fibers.

Selected Publications (from total of 86)

Liu H, Naxerova K, Pinter M, Incio J, Lee H, Shigeta K, Ho WW, Crain JA, Jacobson A, Michelakos T, Dias-Santos D, Zanconato A, Hong TS, Clark JW, Murphy JE, Ryan DP, Deshpande V, Lillemoe KD, Fernandez-Del Castillo C, Downes M, Evans RM, Michaelson J, Ferrone CR, Boucher Y, Jain RK
Use of Angiotensin System Inhibitors is Associated with Immune Activation and Longer Survival in Non-Metastatic Pancreatic Ductal Adenocarcinoma.
Clin Cancer Res. 2017;:ePub - PMID: 28600474
David P. Kodack, Vasileios Askoxylakis, Gino B. Ferraro, Qing Sheng, Mark Badeaux, Shom Goel, Xiaolong Qi, Ram Shankaraiah, Z. Alexander Cao, Rakesh R. Ramjiawan, Divya Bezwada, Bhushankumar Patel, Yongchul Song, Carlotta Costa, Kamila Naxerova, Christina S. F. Wong, Jonas Kloepper, Rita Das, Angela Tam, Jantima Tanboon, Dan G. Duda, C. Ryan Miller, Marni B. Siegel, Carey K. Anders, Melinda Sanders, Monica V. Estrada, Robert Schlegel, Carlos L. Arteaga, Elena Brachtel, Alan Huang, Dai Fukumura, Jeffrey A. Engelman, Rakesh K. Jain
The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation
Science Translational Medicine. 2017;9(391):eaal4682
Martin JD, Fukumura D, Duda DG, Boucher Y, Jain RK
Corrigendum: Reengineering the Tumor Microenvironment to Alleviate Hypoxia and Overcome Cancer Heterogeneity.
Cold Spring Harb Perspect Med. 2016;6(12):ePub - PMID: 27908927 - PMCID: PMC5131752
Rahbari NN, Kedrin D, Incio J, Liu H, Ho WW, Nia HT, Edrich CM, Jung K, Daubriac J, Chen I, Heishi T, Martin JD, Huang Y, Maimon N, Reissfelder C, Weitz J, Boucher Y, Clark JW, Grodzinsky AJ, Duda DG, Jain RK, Fukumura D
Anti-VEGF therapy induces ECM remodeling and mechanical barriers to therapy in colorectal cancer liver metastases.
Sci Transl Med. 2016;8(360):360ra135 - PMID: 27733559 - PMCID: PMC5457741
Kumar V, Boucher Y, Liu H, Ferreira D, Hooker J, Catana C, Hoover AJ, Ritter T, Jain RK, Guimaraes AR
Noninvasive Assessment of Losartan-Induced Increase in Functional Microvasculature and Drug Delivery in Pancreatic Ductal Adenocarcinoma.
Transl Oncol. 2016;9(5):431-437 - PMID: 27751347 - PMCID: PMC5067928
Martin JD, Fukumura D, Duda DG, Boucher Y, Jain RK
Reengineering the Tumor Microenvironment to Alleviate Hypoxia and Overcome Cancer Heterogeneity.
Cold Spring Harb Perspect Med. 2016;:ePub - PMID: 27663981
Incio J, Liu H, Suboj P, Chin SM, Chen IX, Pinter M, Ng MR, Nia HT, Grahovac J, Kao S, Babykutty S, Huang Y, Jung K, Rahbari NN, Han X, Chauhan VP, Martin JD, Kahn J, Huang P, Desphande V, Michaelson J, Michelakos TP, Ferrone CR, Soares R, Boucher Y, Fukumura D, Jain RK
Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy.
Cancer Discov. 2016;6(8):852-69 - PMID: 27246539 - PMCID: PMC4972679
Tolaney SM, Boucher Y, Duda DG, Martin JD, Seano G, Ancukiewicz M, Barry WT, Goel S, Lahdenrata J, Isakoff SJ, Yeh ED, Jain SR, Golshan M, Brock J, Snuderl M, Winer EP, Krop IE, Jain RK
Role of vascular density and normalization in response to neoadjuvant bevacizumab and chemotherapy in breast cancer patients.
Proc Natl Acad Sci U S A. 2015;112(46):14325-14330 - PMID: 26578779 - PMCID: PMC4655544
Ager EI, Kozin SV, Kirkpatrick ND, Seano G, Kodack DP, Askoxylakis V, Huang Y, Goel S, Snuderl M, Muzikansky A, Finkelstein DM, Dransfield DT, Devy L, Boucher Y, Fukumura D, Jain RK
Blockade of MMP14 Activity in Murine Breast Carcinomas: Implications for Macrophages, Vessels, and Radiotherapy.
J Natl Cancer Inst. 2015;107(4):ePub - PMID: 25710962 - PMCID: PMC4402365
Lee JJ, Perera RM, Wang H, Wu DC, Liu XS, Han S, Fitamant J, Jones PD, Ghanta KS, Kawano S, Nagle JM, Deshpande V, Boucher Y, Kato T, Chen JK, Willmann JK, Bardeesy N, Beachy PA
Stromal response to Hedgehog signaling restrains pancreatic cancer progression.
Proc Natl Acad Sci U S A. 2014;111(30):E3091-100 - PMID: 25024225 - PMCID: PMC4121834
Chauhan VP, Boucher Y, Ferrone CR, Roberge S, Martin JD, Stylianopoulos T, Bardeesy N, DePinho RA, Padera TP, Munn LL, Jain RK
Compression of Pancreatic Tumor Blood Vessels by Hyaluronan Is Caused by Solid Stress and Not Interstitial Fluid Pressure.
Cancer Cell. 2014;26(1):14-15 - PMID: 25026209 - PMCID: PMC4381566
Hong TS, Ryan DP, Borger DR, Blaszkowsky LS, Yeap BY, Ancukiewicz M, Deshpande V, Shinagare S, Wo JY, Boucher Y, Wadlow RC, Kwak EL, Allen JN, Clark JW, Zhu AX, Ferrone CR, Mamon HJ, Adams J, Winrich B, Grillo T, Jain RK, DeLaney TF, Fernandez-Del Castillo C, Duda DG
A Phase 1/2 and Biomarker Study of Preoperative Short Course Chemoradiation With Proton Beam Therapy and Capecitabine Followed By Early Surgery for Resectable Pancreatic Ductal Adenocarcinoma.
Int J Radiat Oncol Biol Phys. 2014;89(4):830-8 - PMID: 24867540 - PMCID: PMC4791180
Schwabl P, Payer BA, Grahovac J, Klein S, Horvatits T, Mitterhauser M, Stift J, Boucher Y, Trebicka J, Trauner M, Angermayr B, Fuhrmann V, Reiberger T, Peck-Radosavljevic M
Pioglitazone decreases portosystemic shunting by modulating inflammation and angiogenesis in cirrhotic and non-cirrhotic portal hypertensive rats.
J Hepatol. 2014;60(6):1135-42 - PMID: 24530596
Chauhan VP, Martin JD, Liu H, Lacorre DA, Jain SR, Kozin SV, Stylianopoulos T, Mousa AS, Han X, Adstamongkonkul P, Popovic Z, Huang P, Bawendi MG, Boucher Y, Jain RK
Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels.
Nat Commun. 2013;4:2516 - PMID: 24084631 - PMCID: PMC3806395
Liu J, Liao S, Diop-Frimpong B, Chen W, Goel S, Naxerova K, Ancukiewicz M, Boucher Y, Jain RK, Xu L
TGF-? blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma.
Proc Natl Acad Sci U S A. 2012;109(41):16618-23 - PMID: 22996328 - PMCID: PMC3478596
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