Dual-hit strategy for therapeutic targeting of pancreatic cancer in patient-derived xenograft tumors

Tista Roy Chaudhuri; Qingxiang Lin; Ewa K Stachowiak; Spencer R Rosario; Joseph A Spernyak; Wen Wee Ma; Michal K Stachowiak; Michelle K Greene; Gerard P Quinn; Simon S McDade; Martin Clynes; Christopher J Scott; Robert M Straubinger

doi:10.1158/1078-0432.CCR-23-0131

Dual-hit strategy for therapeutic targeting of pancreatic cancer in patient-derived xenograft tumors

Tista Roy Chaudhuri^*
, Qingxiang Lin
, Ewa K Stachowiak
, Spencer R Rosario
, Joseph A Spernyak
, Wen Wee Ma
, Michal K Stachowiak
, Michelle K Greene
, Gerard P Quinn
, Simon S McDade
, Martin Clynes
, Christopher J Scott
, Robert M Straubinger^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

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Abstract

Purpose
Paracrine activation of pro-fibrotic hedgehog (HH) signaling in pancreatic ductal adenocarcinoma (PDAC) results in stromal amplification that compromises tumor drug delivery, efficacy, and patient survival. Interdiction of HH-mediated tumor-stroma crosstalk with smoothened (SMO) inhibitors (SHHi) “primes” PDAC patient-derived xenograft (PDX) tumors for increased drug delivery by transiently increasing vascular patency/permeability, and thereby macromolecule delivery. However, patient tumor isolates vary in their responsiveness, and responders show co-induction of epithelial–mesenchymal transition (EMT). We aimed to identify the signal derangements responsible for EMT induction and reverse them and devise approaches to stratify SHHi-responsive tumors noninvasively based on clinically-quantifiable parameters.

Experimental design
Animals underwent diffusion-weighted magnetic resonance (DW-MR) imaging for measurement of intratumor diffusivity. In parallel, tissue-level deposition of nanoparticle probes was quantified as a marker of vascular permeability/perfusion. Transcriptomic and bioinformatic analysis was employed to investigate SHHi-induced gene reprogramming and identify key “nodes” responsible for EMT induction.

Results
Multiple patient tumor isolates responded to short-term SHH inhibitor exposure with increased vascular patency and permeability, with proportionate increases in tumor diffusivity. Nonresponding PDXs did not. SHHi-treated tumors showed elevated FGF drive and distinctly higher nuclear localization of fibroblast growth factor receptor (FGFR1) in EMT-polarized tumor cells. Pan-FGFR inhibitor NVP-BGJ398 (Infigratinib) reversed the SHHi-induced EMT marker expression and nuclear FGFR1 accumulation without compromising the enhanced permeability effect.

Conclusions
This dual-hit strategy of SMO and FGFR inhibition provides a clinically-translatable approach to compromise the profound impermeability of PDAC tumors. Furthermore, clinical deployment of DW-MR imaging could fulfill the essential clinical–translational requirement for patient stratification.

Original language	English
Pages (from-to)	1367-1381
Number of pages	15
Journal	Clinical Cancer Research
Volume	30
Issue number	7
Early online date	20 Feb 2024
DOIs	https://doi.org/10.1158/1078-0432.CCR-23-0131
Publication status	Published - 01 Apr 2024

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Cancer Research
Oncology

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10.1158/1078-0432.CCR-23-0131Licence: Unspecified

Dual-hit strategy for therapeutic targeting of pancreatic cancer in patient-derived xenograft tumors
Copyright 2024 American Association for Cancer Research. This is an accepted manuscript distributed under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Accepted author manuscript, 685 KBLicence: CC BY

Cite this

Roy Chaudhuri, T., Lin, Q., Stachowiak, E. K., Rosario, S. R., Spernyak, J. A., Ma, W. W., Stachowiak, M. K., Greene, M. K., Quinn, G. P., McDade, S. S., Clynes, M., Scott, C. J., & Straubinger, R. M. (2024). Dual-hit strategy for therapeutic targeting of pancreatic cancer in patient-derived xenograft tumors. Clinical Cancer Research, 30(7), 1367-1381. https://doi.org/10.1158/1078-0432.CCR-23-0131

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title = "Dual-hit strategy for therapeutic targeting of pancreatic cancer in patient-derived xenograft tumors",

abstract = "Purpose Paracrine activation of pro-fibrotic hedgehog (HH) signaling in pancreatic ductal adenocarcinoma (PDAC) results in stromal amplification that compromises tumor drug delivery, efficacy, and patient survival. Interdiction of HH-mediated tumor-stroma crosstalk with smoothened (SMO) inhibitors (SHHi) “primes” PDAC patient-derived xenograft (PDX) tumors for increased drug delivery by transiently increasing vascular patency/permeability, and thereby macromolecule delivery. However, patient tumor isolates vary in their responsiveness, and responders show co-induction of epithelial–mesenchymal transition (EMT). We aimed to identify the signal derangements responsible for EMT induction and reverse them and devise approaches to stratify SHHi-responsive tumors noninvasively based on clinically-quantifiable parameters. Experimental design Animals underwent diffusion-weighted magnetic resonance (DW-MR) imaging for measurement of intratumor diffusivity. In parallel, tissue-level deposition of nanoparticle probes was quantified as a marker of vascular permeability/perfusion. Transcriptomic and bioinformatic analysis was employed to investigate SHHi-induced gene reprogramming and identify key “nodes” responsible for EMT induction. Results Multiple patient tumor isolates responded to short-term SHH inhibitor exposure with increased vascular patency and permeability, with proportionate increases in tumor diffusivity. Nonresponding PDXs did not. SHHi-treated tumors showed elevated FGF drive and distinctly higher nuclear localization of fibroblast growth factor receptor (FGFR1) in EMT-polarized tumor cells. Pan-FGFR inhibitor NVP-BGJ398 (Infigratinib) reversed the SHHi-induced EMT marker expression and nuclear FGFR1 accumulation without compromising the enhanced permeability effect. Conclusions This dual-hit strategy of SMO and FGFR inhibition provides a clinically-translatable approach to compromise the profound impermeability of PDAC tumors. Furthermore, clinical deployment of DW-MR imaging could fulfill the essential clinical–translational requirement for patient stratification. ",

keywords = "Cancer Research, Oncology",

author = "\{Roy Chaudhuri\}, Tista and Qingxiang Lin and Stachowiak, \{Ewa K\} and Rosario, \{Spencer R\} and Spernyak, \{Joseph A\} and Ma, \{Wen Wee\} and Stachowiak, \{Michal K\} and Greene, \{Michelle K\} and Quinn, \{Gerard P\} and McDade, \{Simon S\} and Martin Clynes and Scott, \{Christopher J\} and Straubinger, \{Robert M\}",

year = "2024",

month = apr,

day = "1",

doi = "10.1158/1078-0432.CCR-23-0131",

language = "English",

volume = "30",

pages = "1367--1381",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "7",

}

Roy Chaudhuri, T, Lin, Q, Stachowiak, EK, Rosario, SR, Spernyak, JA, Ma, WW, Stachowiak, MK, Greene, MK, Quinn, GP, McDade, SS, Clynes, M, Scott, CJ & Straubinger, RM 2024, 'Dual-hit strategy for therapeutic targeting of pancreatic cancer in patient-derived xenograft tumors', Clinical Cancer Research, vol. 30, no. 7, pp. 1367-1381. https://doi.org/10.1158/1078-0432.CCR-23-0131

TY - JOUR

T1 - Dual-hit strategy for therapeutic targeting of pancreatic cancer in patient-derived xenograft tumors

AU - Roy Chaudhuri, Tista

AU - Lin, Qingxiang

AU - Stachowiak, Ewa K

AU - Rosario, Spencer R

AU - Spernyak, Joseph A

AU - Ma, Wen Wee

AU - Stachowiak, Michal K

AU - Greene, Michelle K

AU - Quinn, Gerard P

AU - McDade, Simon S

AU - Clynes, Martin

AU - Scott, Christopher J

AU - Straubinger, Robert M

PY - 2024/4/1

Y1 - 2024/4/1

N2 - Purpose Paracrine activation of pro-fibrotic hedgehog (HH) signaling in pancreatic ductal adenocarcinoma (PDAC) results in stromal amplification that compromises tumor drug delivery, efficacy, and patient survival. Interdiction of HH-mediated tumor-stroma crosstalk with smoothened (SMO) inhibitors (SHHi) “primes” PDAC patient-derived xenograft (PDX) tumors for increased drug delivery by transiently increasing vascular patency/permeability, and thereby macromolecule delivery. However, patient tumor isolates vary in their responsiveness, and responders show co-induction of epithelial–mesenchymal transition (EMT). We aimed to identify the signal derangements responsible for EMT induction and reverse them and devise approaches to stratify SHHi-responsive tumors noninvasively based on clinically-quantifiable parameters. Experimental design Animals underwent diffusion-weighted magnetic resonance (DW-MR) imaging for measurement of intratumor diffusivity. In parallel, tissue-level deposition of nanoparticle probes was quantified as a marker of vascular permeability/perfusion. Transcriptomic and bioinformatic analysis was employed to investigate SHHi-induced gene reprogramming and identify key “nodes” responsible for EMT induction. Results Multiple patient tumor isolates responded to short-term SHH inhibitor exposure with increased vascular patency and permeability, with proportionate increases in tumor diffusivity. Nonresponding PDXs did not. SHHi-treated tumors showed elevated FGF drive and distinctly higher nuclear localization of fibroblast growth factor receptor (FGFR1) in EMT-polarized tumor cells. Pan-FGFR inhibitor NVP-BGJ398 (Infigratinib) reversed the SHHi-induced EMT marker expression and nuclear FGFR1 accumulation without compromising the enhanced permeability effect. Conclusions This dual-hit strategy of SMO and FGFR inhibition provides a clinically-translatable approach to compromise the profound impermeability of PDAC tumors. Furthermore, clinical deployment of DW-MR imaging could fulfill the essential clinical–translational requirement for patient stratification.

AB - Purpose Paracrine activation of pro-fibrotic hedgehog (HH) signaling in pancreatic ductal adenocarcinoma (PDAC) results in stromal amplification that compromises tumor drug delivery, efficacy, and patient survival. Interdiction of HH-mediated tumor-stroma crosstalk with smoothened (SMO) inhibitors (SHHi) “primes” PDAC patient-derived xenograft (PDX) tumors for increased drug delivery by transiently increasing vascular patency/permeability, and thereby macromolecule delivery. However, patient tumor isolates vary in their responsiveness, and responders show co-induction of epithelial–mesenchymal transition (EMT). We aimed to identify the signal derangements responsible for EMT induction and reverse them and devise approaches to stratify SHHi-responsive tumors noninvasively based on clinically-quantifiable parameters. Experimental design Animals underwent diffusion-weighted magnetic resonance (DW-MR) imaging for measurement of intratumor diffusivity. In parallel, tissue-level deposition of nanoparticle probes was quantified as a marker of vascular permeability/perfusion. Transcriptomic and bioinformatic analysis was employed to investigate SHHi-induced gene reprogramming and identify key “nodes” responsible for EMT induction. Results Multiple patient tumor isolates responded to short-term SHH inhibitor exposure with increased vascular patency and permeability, with proportionate increases in tumor diffusivity. Nonresponding PDXs did not. SHHi-treated tumors showed elevated FGF drive and distinctly higher nuclear localization of fibroblast growth factor receptor (FGFR1) in EMT-polarized tumor cells. Pan-FGFR inhibitor NVP-BGJ398 (Infigratinib) reversed the SHHi-induced EMT marker expression and nuclear FGFR1 accumulation without compromising the enhanced permeability effect. Conclusions This dual-hit strategy of SMO and FGFR inhibition provides a clinically-translatable approach to compromise the profound impermeability of PDAC tumors. Furthermore, clinical deployment of DW-MR imaging could fulfill the essential clinical–translational requirement for patient stratification.

KW - Cancer Research

KW - Oncology

U2 - 10.1158/1078-0432.CCR-23-0131

DO - 10.1158/1078-0432.CCR-23-0131

M3 - Article

C2 - 38270582

SN - 1078-0432

VL - 30

SP - 1367

EP - 1381

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 7

ER -

Dual-hit strategy for therapeutic targeting of pancreatic cancer in patient-derived xenograft tumors

Abstract

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