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

Abstract

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.

The pivotal application of patient-derived organoid biobanks for personalized treatment of gastrointestinal cancers

“… [ 97 ] PDCA MEK, HSP-90 CTG The inhibition of HSP-90 increases the anti-cancer activity of MEK inhibition in PDOX model by overcoming the compensatory activation of resistance pathways induced by MEK inhibition. [ 98 ] PDAC DCLK1 CTG DCLK1-IN-1, the first selective probe of the DCLK1 kinase domain, shows anti-cancer activity in PDAC PDOs by modulating cell motility related proteins. [ 99 ] GC STAT3, VEGFR, ATR, PARP, SMO, EGFR, ARID1A, CDK4/6, MEK, RAF, PI3K, mTOR, HER2, HGFR, WNT, BCR, CDK, TNF-a, TTK, PLK CTG The GC PDOs shows good responses to some new target drugs and some target drugs currently in clinical trials.…”

“…SHP2 activation was important resistance mechanism for blockade of MEK in KRAS-mutant cancer, and there were synergy effects between SHP2 and MEK inhibitions in PDOs of PDAC, indicating that the dual SHP2/MEK inhibitors may be applied to the treatment for KRAS-mutant PDAC patients [ 95 ]. The inhibition of heat shock protein (HSP)-90 increases the anti-cancer activity of MEK inhibition in PDOX model by overcoming the compensatory activation of resistance pathways, such as PI3K/AKT/mTOR signaling, induced by MEK inhibition [ 98 ]. Both NHWD-870 and JQ1(the inhibitors of c-MYC transcription) were efficient in MYC-high samples using PDAC PDOs, while NHWD-870 was the more effective, indicating that the combination of the molecular signatures and drug screening of PDAC PDOs could be applied to find optimal therapy for each patient in a clinical timeframe [ 109 ].…”

Modeling pancreatic cancer in mice for experimental therapeutics

“…Thus, considering these points during OT implantation in the mouse pancreas would help in more appropriate and non-erroneous assessment of therapeutic modalities. Recently, OT mouse model was used for mass screening of > 50 drugs and the study concluded that the combination of HSP70 and MEK inhibitors exerts synergistic effect against PDAC and could be taken for further evaluation [117].…”

Hydrogels to engineer tumor microenvironmentsin vitro

“…To date, an immense collection of patient-derived tumor organoids for long-term cultures have been generated and biobanked, including cancers of the lung, 47 breast, 48 gastrointestinal tissues, 49 and pancreas. 50 As these tumor organoid models reflect the molecular profile and inherent heterogeneity in cancer cells found in the corresponding patient, 48 these organoids present tremendous opportunities for drug development and personalized drug testing. In a landmark study by Vlachogiannis and colleagues, the authors established gastrointestinal organoid cultures, treated them with drugs used in patients, and obtained 93% specificity and 88% positive predictive values, suggesting that these models may be very useful for personalized drug testing.…”