Antitumor Activity of Targeted and Cytotoxic Agents in Murine Subcutaneous Tumor Models Correlates with Clinical Response

Wong, Harvey; Choo, Edna F.; Alicke, Bruno; Ding, Xiao; La, Hank; McNamara, Erin; Theil, Frank‐Peter; Tibbitts, Jay; Friedman, Lori S.; Hop, Cornelis E. C. A.; Gould, Stephen E.

doi:10.1158/1078-0432.ccr-12-0738

Cited by 120 publications

(123 citation statements)

References 33 publications

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“…2, blue bars). BHPI easily exceeded the goal of >60% tumor growth inhibition proposed as a benchmark more likely to lead to clinical response (20). Furthermore, BHPI, at 10 mg/kg every other day, ultimately stopped tumor growth and final tumor weight was reduced ∼60% compared with controls (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 99%

Estrogen receptor α inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression

Andruska¹,

Zheng²,

Yang³

et al. 2015

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

140

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Recurrent estrogen receptor α (ERα)-positive breast and ovarian cancers are often therapy resistant. Using screening and functional validation, we identified BHPI, a potent noncompetitive small molecule ERα biomodulator that selectively blocks proliferation of drug-resistant ERα-positive breast and ovarian cancer cells. In a mouse xenograft model of breast cancer, BHPI induced rapid and substantial tumor regression. Whereas BHPI potently inhibits nuclear estrogen-ERα-regulated gene expression, BHPI is effective because it elicits sustained ERα-dependent activation of the endoplasmic reticulum (EnR) stress sensor, the unfolded protein response (UPR), and persistent inhibition of protein synthesis. BHPI distorts a newly described action of estrogen-ERα: mild and transient UPR activation. In contrast, BHPI elicits massive and sustained UPR activation, converting the UPR from protective to toxic. In ERα + cancer cells, BHPI rapidly hyperactivates plasma membrane PLCγ, generating inositol 1,4,5-triphosphate (IP 3 ), which opens EnR IP 3 R calcium channels, rapidly depleting EnR Ca 2+ stores. This leads to activation of all three arms of the UPR. Activation of the PERK arm stimulates phosphorylation of eukaryotic initiation factor 2α (eIF2α), resulting in rapid inhibition of protein synthesis. The cell attempts to restore EnR Ca 2+ levels, but the open EnR IP 3 R calcium channel leads to an ATP-depleting futile cycle, resulting in activation of the energy sensor AMP-activated protein kinase and phosphorylation of eukaryotic elongation factor 2 (eEF2). eEF2 phosphorylation inhibits protein synthesis at a second site. BHPI's novel mode of action, high potency, and effectiveness in therapyresistant tumor cells make it an exceptional candidate for further mechanistic and therapeutic exploration.estrogen receptor | drug discovery | breast cancer | unfolded protein response | ovarian cancer E strogens, acting via estrogen receptor α (ERα), stimulate tumor growth (1-3). Approximately 70% of breast cancers are ERα-positive and most deaths due to breast cancer are in patients with ERα + tumors (2, 4). Endocrine therapy using aromatase inhibitors to block estrogen production, or tamoxifen and other competitor antiestrogens, often results in selection and outgrowth of resistant tumors. Although 30-70% of epithelial ovarian tumors are ERα-positive (1), endocrine therapy is largely ineffective (5-7). After several cycles of chemotherapy, tumors recur as resistant ovarian cancer (5), and most patients die within 5 years (8).Noncompetitive ERα inhibitors targeting this unmet therapeutic need, including DIBA, TPBM, TPSF, and LRH-1 inhibitors that reduce ERα levels, show limited specificity, require high concentrations (>5 μM), and usually have not advanced through preclinical development (9-12). These noncompetitive ERα inhibitors and competitor antiestrogens are primarily cytostatic and act by preventing estrogen-ERα action; therefore, they are largely ineffective in therapy-resistant ERα containing cancer cells that no longer requi...

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Section: Resultsmentioning

confidence: 99%

Estrogen receptor α inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression

Andruska¹,

Zheng²,

Yang³

et al. 2015

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

140

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“…It has been reported that preclinical efficacy in xenografts may predict the clinical efficacy. 23,24 Therefore, understanding the exposureresponse relationship for drug candidates in a preclinical model could aid in predicting the optimal dose and regimen in patients. 25 For example, the active plasma concentration of cetuximab in a mouse xenograft model was fairly comparable with those observed in patients.…”

Section: Discussionmentioning

confidence: 99%

Preclinical pharmacokinetics, pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 monoclonal antibody, an immune checkpoint inhibitor

Deng¹,

Bumbaca²,

Pastuskovas³

et al. 2016

mAbs

172

167

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MPDL3280A is a human monoclonal antibody that targets programmed cell death-1 ligand 1 (PD-L1), and exerts anti-tumor activity mainly by blocking PD-L1 interaction with programmed cell death-1 (PD-1) and B7.1. It is being investigated as a potential therapy for locally advanced or metastatic malignancies. The purpose of the study reported here was to characterize the pharmacokinetics, pharmacodynamics, tissue distribution and tumor penetration of MPDL3280A and/or a chimeric anti-PD-L1 antibody PRO304397 to help further clinical development.The pharmacokinetics of MPDL3280A in monkeys at 0.5, 5 and 20 mg¢kg ¡1 and the pharmacokinetics / pharmacodynamics of PRO304397 in mice at 1, 3 10 mg¢kg ¡1 were determined after a single intravenous dose. Tissue distribution and tumor penetration for radiolabeled PRO304397 in tumor-bearing mouse models were determined.The pharmacokinetics of MPDL3280A and PRO304397 were nonlinear in monkeys and mice, respectively. Complete saturation of PD-L1 in blood in mice was achieved at serum concentrations of PRO304397 above »0.5 mg¢mL ¡1 . Tissue distribution and tumor penetration studies of PRO304397 in tumor-bearing mice indicated that the minimum tumor interstitial to plasma radioactivity ratio was »0.3; saturation of target-mediated uptake in non-tumor tissues and desirable exposure in tumors were achieved at higher serum concentrations, and the distribution into tumors was dose-and time-dependent.The biodistribution data indicated that the efficacious dose is mostly likely higher than that estimated based on simple pharmacokinetics/pharmacodynamics in blood. These data also allowed for estimation of the target clinical dose for further development of MPDL3280A.

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“…Tumor xenografted mice serve as a "workhorse" efficacy model to assess antitumor effects of novel agents and thus are widely used in oncology drug discovery (Johnson et al, 2001;Kelland, 2004;Peterson and Houghton, 2004;Wong et al, 2012b). Our previous investigation showed that a correlation exists between antitumor activity in xenografted/allografted mice and clinical response, provided that two conditions were fulfilled.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous investigation showed that a correlation exists between antitumor activity in xenografted/allografted mice and clinical response, provided that two conditions were fulfilled. These conditions were 1) that species differences in mouse and human PK had to be normalized, and 2) that the specific xenograft model used in the assessment had to be relevant to human disease being treated (Wong et al, 2012b). At the time of our work with GDC-0917, we arbitrarily set ED 50 and ED 90 as two efficacy end points from which we would evaluate the compound in a breast cancer model.…”

Section: Discussionmentioning

confidence: 99%

Learning and Confirming with Preclinical Studies: Modeling and Simulation in the Discovery of GDC-0917, an Inhibitor of Apoptosis Proteins Antagonist

et al. 2013

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The application of modeling and simulation techniques is increasingly common in the preclinical stages of the drug development process.is a potent second-generation antagonist of inhibitor of apoptosis (IAP) proteins that is being developed for the treatment of various cancers. GDC-0917 has low to moderate clearance in the mouse (12.0 ml/min/ kg), rat (27.0 ml/min/kg), and dog (15.3 ml/min/kg), and high clearance in the monkey (67.6 ml/min/kg). Accordingly, oral bioavailability was lowest in monkeys compared with other species. Based on our experience with a prototype molecule with similar structure, in vitroin vivo extrapolation was used to predict a moderate clearance (11.5 ml/min/kg) in humans. The predicted human volume of distribution was estimated using simple allometry at 6.69 l/kg. Translational pharmacokinetic-pharmacodynamic (PK-PD) analysis using results from MDA-MB-231-X1.1 breast cancer xenograft studies and predicted human pharmacokinetics suggests that ED 50 and ED 90 targets can be achieved in humans using acceptable doses (72 mg and 660 mg, respectively) and under an acceptable time frame. The relationship between GDC-0917 concentrations and pharmacodynamic response (cIAP1 degradation) was characterized using an in vitro peripheral blood mononuclear cell immunoassay. Simulations of human GDC-0917 plasma concentration-time profile and cIAP1 degradation at the 5-mg starting dose in the phase 1 clinical trial agreed well with observations. This work shows the importance of leveraging information from prototype molecules and illustrates how modeling and simulation can be used to add value to preclinical studies in the early stages of the drug development process.

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Antitumor Activity of Targeted and Cytotoxic Agents in Murine Subcutaneous Tumor Models Correlates with Clinical Response

Cited by 120 publications

References 33 publications

Estrogen receptor α inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression

Estrogen receptor α inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression

Preclinical pharmacokinetics, pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 monoclonal antibody, an immune checkpoint inhibitor

Learning and Confirming with Preclinical Studies: Modeling and Simulation in the Discovery of GDC-0917, an Inhibitor of Apoptosis Proteins Antagonist

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