Paradigms for Precision Medicine in Epichaperome Cancer Therapy

Pillarsetty, Nagavarakishore; Jhaveri, Komal; Taldone, Tony; Caldas‐Lopes, Eloisi; Punzalan, Blesida; Joshi, Suhasini; Bolaender, Alexander; Uddin, Mohammad M.; Rodina, Anna; Yan, Ping; Ku, Anson T.; Ku, Thomas W.; Shah, Smit; Lyashchenko, Serge K.; Burnazi, Eva; Wang, Tai; Lecomte, Nicolas; Janjigian, Yelena Y.; Younes, Anas; Batlevi, Connie W; Guzmán, Mónica L.; Roboz, Gail J.; Koziorowski, Jacek; Zanzonico, Pat; Alpaugh, Mary L.; Corben, Adriana D.; Modi, Shanu; Norton, Larry; Larson, Steven M.; Lewis, Jason S.; Chiosis, Gabriela; Gerecitano, John F.; Dunphy, Mark

doi:10.1016/j.ccell.2019.09.007

Cited by 47 publications

(112 citation statements)

References 46 publications

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“…1C). However, several drugs, including gemcitabine (GEM), trametinib, a MAPK/ERK kinase (MEK)-1/2 inhibitor, and PU-H71, a heatshock protein (HSP)-90 inhibitor with specificity for tumor HSP90 variants (11)(12)(13)(14), significantly reduced tumor growth when compared to control.…”

Section: Resultsmentioning

confidence: 99%

Unbiased in vivo preclinical evaluation of anticancer drugs identifies effective therapy for the treatment of pancreatic adenocarcinoma

Grbovic-Huezo

Pitter

Lecomte

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed at an advanced stage, which limits surgical options and portends a dismal prognosis. Current oncologic PDAC therapies confer marginal benefit and, thus, a significant unmet clinical need exists for new therapeutic strategies. To identify effective PDAC therapies, we leveraged a syngeneic orthotopic PDAC transplant mouse model to perform a large-scale, in vivo screen of 16 single-agent and 41 two-drug targeted therapy combinations in mice. Among 57 drug conditions screened, combined inhibition of heat shock protein (Hsp)-90 and MEK was found to produce robust suppression of tumor growth, leading to an 80% increase in the survival of PDAC-bearing mice with no significant toxicity. Mechanistically, we observed that single-agent MEK inhibition led to compensatory activation of resistance pathways, including components of the PI3K/AKT/mTOR signaling axis, which was overcome with the addition of HSP90 inhibition. The combination of HSP90(i) + MEK(i) was also active in vitro in established human PDAC cell lines and in vivo in patient-derived organoid PDAC transplant models. These findings encourage the clinical development of HSP90(i) + MEK(i) combination therapy and highlight the power of clinically relevant in vivo model systems for identifying cancer therapies.

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Section: Resultsmentioning

confidence: 99%

Unbiased in vivo preclinical evaluation of anticancer drugs identifies effective therapy for the treatment of pancreatic adenocarcinoma

Grbovic-Huezo

Pitter

Lecomte

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…For example, PU-H71 kinetically selects for epichaperome-integrated HSP90; no epichaperome IHC assay exists and histologic HSP90 expression is not predictive. Tumor avidity for PU-H71 tracer predicts pharmacodynamics and efficacy for PU-H71 [ 7 , 8 , 49 , 68 , 69 , 86 ] and other small molecule drugs targeting the HSP90 ATPase and interfering with epichaperome formation [ 8 , 49 ].…”

Section: Drug Tracer Imaging To Guide Patient Selectionmentioning

confidence: 99%

“…Drug tracer imaging can assay tumor pharmacokinetics, including (1) tumor drug concentrations as a function of time post-drug administration and (2) tumor occupancy by therapeutic drug doses [ 87 ]. Tumor pharmacokinetic data from patient imaging can be mathematically modeled for predicting the therapeutic dosage and schedule needed to achieve desired in vivo tumor drug concentration and tumor saturation levels [ 8 , 49 ] ( Figure 3 ). Imaging biodistribution can help to establish correlations with observed organ toxicity that might enable dosing strategies optimized for the therapeutic index [ 65 ].…”

Section: Tumor Pharmacokinetics For Image-guided Dosing Designmentioning

confidence: 99%

“…We and others have explored clinical PET-based approaches to quantifying in vivo tumor drug molar concentrations [ 8 , 37 , 49 , 95 ]. Ideally, for tracing pharmacokinetics, drug tracer and (non-labeled) therapeutic drugs are isotopologues, as drug and tracer should then have identical physicochemical characteristics ( Figure 1 ).…”

Section: Tumor Pharmacokinetics For Image-guided Dosing Designmentioning

confidence: 99%

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The Unique Pharmacometrics of Small Molecule Therapeutic Drug Tracer Imaging for Clinical Oncology

Dunphy

Pillarsetty

2020

Cancers

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Translational development of radiolabeled analogues or isotopologues of small molecule therapeutic drugs as clinical imaging biomarkers for optimizing patient outcomes in targeted cancer therapy aims to address an urgent and recurring clinical need in therapeutic cancer drug development: drug- and target-specific biomarker assays that can optimize patient selection, dosing strategy, and response assessment. Imaging the in vivo tumor pharmacokinetics and biomolecular pharmacodynamics of small molecule cancer drugs offers patient- and tumor-specific data which are not available from other pharmacometric modalities. This review article examines clinical research with a growing pharmacopoeia of investigational small molecule cancer drug tracers.

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“…Radiodiagnostics, such as PET imaging, has emerged as a vital component in precision medicine. [1][2][3][4][5][6][7] Several radiotracers have been used extensively for patient stratification and prognosis assessment in clinical settings. Besides, numerous radiotracers are being studied in clinical trials or are under pre-clinical evaluation.…”

Section: Introductionmentioning

confidence: 99%

Harnessing the PD-L1 interface peptide for positron emission tomography imaging of the PD-1 immune checkpoint

Xie

Hanyu

et al. 2020

RSC Chem. Biol.

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Paradigms for Precision Medicine in Epichaperome Cancer Therapy

Cited by 47 publications

References 46 publications

Unbiased in vivo preclinical evaluation of anticancer drugs identifies effective therapy for the treatment of pancreatic adenocarcinoma

Unbiased in vivo preclinical evaluation of anticancer drugs identifies effective therapy for the treatment of pancreatic adenocarcinoma

The Unique Pharmacometrics of Small Molecule Therapeutic Drug Tracer Imaging for Clinical Oncology

Harnessing the PD-L1 interface peptide for positron emission tomography imaging of the PD-1 immune checkpoint

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