CASPER: A Phase I trial combining calaspargase pegol-mnkl and cobimetinib in pancreatic cancer

Charles D. Lopez; Adel Kardosh; Emerson Y. Chen; Guillaume Pegna; Alexander Guimaraes; Bryan Foster; Brian Brinkerhoff; Shaun M. Goodyear; Jeong Youn Lim; Erin Taber; Brindha Rajagopalan; Exodus Edmerson; Johnson Vo; Katherine Nelson; Anna Jackson; Tasha Gingerich; Anne Fahlman; Christopher Lessenich; Francesca Fennell; Diane Ventura; Preeyam Roy; Dove Keith; Brett Sheppard; Jonathan R. Brody; Gordon B. Mills; Ze'ev A. Ronai; Rosalie C. Sears

doi:10.1080/14796694.2024.2395235

CASPER: A Phase I trial combining calaspargase pegol-mnkl and cobimetinib in pancreatic cancer

Charles D. Lopez, Adel Kardosh, Emerson Y. Chen, Guillaume Pegna, Alexander Guimaraes, Bryan Foster, Brian Brinkerhoff, Shaun M. Goodyear, Jeong Youn Lim, Erin Taber, Brindha Rajagopalan, Exodus Edmerson, Johnson Vo, Katherine Nelson, Anna Jackson, Tasha Gingerich, Anne Fahlman, Christopher Lessenich, Francesca Fennell, Diane VenturaPreeyam Roy, Dove Keith, Brett Sheppard, Jonathan R. Brody, Gordon B. Mills, Ze'ev A. Ronai, Rosalie C. Sears

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

Abstract

Asparagine synthetase (ASNS) catalyzes the biosynthesis of asparagine from aspartate and glutamine. Cells lacking ASNS, however, are auxotrophic for asparagine. Use of L-asparaginase to promote asparagine starvation in solid tumors with low ASNS levels, such as pancreatic ductal adenocarcinoma (PDAC), is a rationale treatment strategy. However, tumor cell resistance to L-asparaginase has limited its clinical utility. Our preclinical studies show that RAS/MAPK signaling circumvents L-asparaginase-induced tumor killing, but L-asparaginase and MEK inhibition potentiated tumor killing; suggesting that this combination may provide meaningful clinical benefit to patients with PDAC. This Phase I trial (NCT05034627) will evaluate the safety and tolerability of the MEK inhibitor, cobimetinib, in combination with pegylated L-asparaginase, L calaspargase pegol-mknl, in patients with locally-advanced or metastatic PDAC.

Original language	English (US)
Pages (from-to)	2915-2925
Number of pages	11
Journal	Future Oncology
Volume	20
Issue number	37
DOIs	https://doi.org/10.1080/14796694.2024.2395235
State	Published - 2024

Keywords

L-asparaginase
MEK inhibition
calaspargase pegol-mknl
cobimetinib
drug resistance
metabolic reprogramming
pancreatic cancer

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1080/14796694.2024.2395235

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Lopez, C. D., Kardosh, A., Chen, E. Y., Pegna, G., Guimaraes, A., Foster, B., Brinkerhoff, B., Goodyear, S. M., Lim, J. Y., Taber, E., Rajagopalan, B., Edmerson, E., Vo, J., Nelson, K., Jackson, A., Gingerich, T., Fahlman, A., Lessenich, C., Fennell, F., ... Sears, R. C. (2024). CASPER: A Phase I trial combining calaspargase pegol-mnkl and cobimetinib in pancreatic cancer. Future Oncology, 20(37), 2915-2925. https://doi.org/10.1080/14796694.2024.2395235

Lopez, CD , Kardosh, A , Chen, EY , Pegna, G , Guimaraes, A , Foster, B , Brinkerhoff, B, Goodyear, SM, Lim, JY, Taber, E, Rajagopalan, B, Edmerson, E, Vo, J, Nelson, K, Jackson, A, Gingerich, T, Fahlman, A, Lessenich, C, Fennell, F, Ventura, D, Roy, P, Keith, D, Sheppard, B , Brody, JR , Mills, GB, Ronai, ZA & Sears, RC 2024, 'CASPER: A Phase I trial combining calaspargase pegol-mnkl and cobimetinib in pancreatic cancer', Future Oncology, vol. 20, no. 37, pp. 2915-2925. https://doi.org/10.1080/14796694.2024.2395235

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title = "CASPER: A Phase I trial combining calaspargase pegol-mnkl and cobimetinib in pancreatic cancer",

abstract = "Asparagine synthetase (ASNS) catalyzes the biosynthesis of asparagine from aspartate and glutamine. Cells lacking ASNS, however, are auxotrophic for asparagine. Use of L-asparaginase to promote asparagine starvation in solid tumors with low ASNS levels, such as pancreatic ductal adenocarcinoma (PDAC), is a rationale treatment strategy. However, tumor cell resistance to L-asparaginase has limited its clinical utility. Our preclinical studies show that RAS/MAPK signaling circumvents L-asparaginase-induced tumor killing, but L-asparaginase and MEK inhibition potentiated tumor killing; suggesting that this combination may provide meaningful clinical benefit to patients with PDAC. This Phase I trial (NCT05034627) will evaluate the safety and tolerability of the MEK inhibitor, cobimetinib, in combination with pegylated L-asparaginase, L calaspargase pegol-mknl, in patients with locally-advanced or metastatic PDAC.",

keywords = "L-asparaginase, MEK inhibition, calaspargase pegol-mknl, cobimetinib, drug resistance, metabolic reprogramming, pancreatic cancer",

author = "Lopez, {Charles D.} and Adel Kardosh and Chen, {Emerson Y.} and Guillaume Pegna and Alexander Guimaraes and Bryan Foster and Brian Brinkerhoff and Goodyear, {Shaun M.} and Lim, {Jeong Youn} and Erin Taber and Brindha Rajagopalan and Exodus Edmerson and Johnson Vo and Katherine Nelson and Anna Jackson and Tasha Gingerich and Anne Fahlman and Christopher Lessenich and Francesca Fennell and Diane Ventura and Preeyam Roy and Dove Keith and Brett Sheppard and Brody, {Jonathan R.} and Mills, {Gordon B.} and Ronai, {Ze'ev A.} and Sears, {Rosalie C.}",

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year = "2024",

doi = "10.1080/14796694.2024.2395235",

language = "English (US)",

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T2 - A Phase I trial combining calaspargase pegol-mnkl and cobimetinib in pancreatic cancer

AU - Lopez, Charles D.

AU - Kardosh, Adel

AU - Chen, Emerson Y.

AU - Pegna, Guillaume

AU - Guimaraes, Alexander

AU - Foster, Bryan

AU - Brinkerhoff, Brian

AU - Goodyear, Shaun M.

AU - Lim, Jeong Youn

AU - Taber, Erin

AU - Rajagopalan, Brindha

AU - Edmerson, Exodus

AU - Vo, Johnson

AU - Nelson, Katherine

AU - Jackson, Anna

AU - Gingerich, Tasha

AU - Fahlman, Anne

AU - Lessenich, Christopher

AU - Fennell, Francesca

AU - Ventura, Diane

AU - Roy, Preeyam

AU - Keith, Dove

AU - Sheppard, Brett

AU - Brody, Jonathan R.

AU - Mills, Gordon B.

AU - Ronai, Ze'ev A.

AU - Sears, Rosalie C.

PY - 2024

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AB - Asparagine synthetase (ASNS) catalyzes the biosynthesis of asparagine from aspartate and glutamine. Cells lacking ASNS, however, are auxotrophic for asparagine. Use of L-asparaginase to promote asparagine starvation in solid tumors with low ASNS levels, such as pancreatic ductal adenocarcinoma (PDAC), is a rationale treatment strategy. However, tumor cell resistance to L-asparaginase has limited its clinical utility. Our preclinical studies show that RAS/MAPK signaling circumvents L-asparaginase-induced tumor killing, but L-asparaginase and MEK inhibition potentiated tumor killing; suggesting that this combination may provide meaningful clinical benefit to patients with PDAC. This Phase I trial (NCT05034627) will evaluate the safety and tolerability of the MEK inhibitor, cobimetinib, in combination with pegylated L-asparaginase, L calaspargase pegol-mknl, in patients with locally-advanced or metastatic PDAC.

KW - L-asparaginase

KW - MEK inhibition

KW - calaspargase pegol-mknl

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CASPER: A Phase I trial combining calaspargase pegol-mnkl and cobimetinib in pancreatic cancer

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