Generalized Additive Mixed Modeling of Longitudinal Tumor Growth Reduces Bias and Improves Decision Making in Translational Oncology

Forrest, William F.; Alicke, Bruno; Mayba, Oleg; Osińska, Magdalena; Jakubczak, Michał; Piatkowski, Pawel; Choniawko, Lech; Starr, Alice; Gould, Stephen E.

doi:10.1158/0008-5472.can-20-0342

Cited by 13 publications

(17 citation statements)

References 45 publications

(34 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Analysis and comparison of tumor growth was performed as detailed previously using a package of customized functions in R v3.6.2 (R Development Core Team 2008; R Foundation for Statistical Computing, Vienna, Austria) which integrate software from open source packages including lme4, mgcv, gamm4, multcomp, settings, plyr, and several packages from the tidyverse such as magrittr, dplyr, tidyr, and ggplot2 8 , 59 . In brief, as tumors generally exhibit exponential growth, tumor volumes were subjected to natural log transformation before analysis.…”

Section: Methodsmentioning

confidence: 99%

Distinct resistance mechanisms arise to allosteric vs. ATP-competitive AKT inhibitors

et al. 2022

View full text Add to dashboard Cite

The AKT kinases have emerged as promising therapeutic targets in oncology and both allosteric and ATP-competitive AKT inhibitors have entered clinical investigation. However, long-term efficacy of such inhibitors will likely be challenged by the development of resistance. We have established prostate cancer models of acquired resistance to the allosteric inhibitor MK-2206 or the ATP-competitive inhibitor ipatasertib following prolonged exposure. While alterations in AKT are associated with acquired resistance to MK-2206, ipatasertib resistance is driven by rewired compensatory activity of parallel signaling pathways. Importantly, MK-2206 resistance can be overcome by treatment with ipatasertib, while ipatasertib resistance can be reversed by co-treatment with inhibitors of pathways including PIM signaling. These findings demonstrate that distinct resistance mechanisms arise to the two classes of AKT inhibitors and that combination approaches may reverse resistance to ATP-competitive inhibition.

show abstract

Section: Methodsmentioning

confidence: 99%

Distinct resistance mechanisms arise to allosteric vs. ATP-competitive AKT inhibitors

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Furthermore, TGR can be generalized to nonexponential growth by replacing the exponential growth rate with any growth rate metric, such as the end point Gain Integrated in Time. 25 …”

Section: Resultsmentioning

confidence: 99%

Growth‐rate model predicts in vivo tumor response from in vitro data

Diegmiller

Salphati²,

Alicke³

et al. 2022

CPT Pharmacom & Syst Pharma

Self Cite

View full text Add to dashboard Cite

show abstract

“…Analysis and comparison of tumor growth was performed as detailed previously using a package of customized functions in R version 3.6.2 (R Development Core Team 2008, R Foundation for Statistical Computing, Vienna, Austria), which integrate software from open-source packages including lme4, mgcv, gamm4, multcomp, settings, and plyr and several packages from the tidyverse such as magrittr, dplyr, tidyr, and ggplot2 ( 54 ). In brief, because tumors generally exhibit exponential growth, tumor volumes were subjected to natural log transformation before analysis.…”

Section: Methodsmentioning

confidence: 99%

Giredestrant reverses progesterone hypersensitivity driven by estrogen receptor mutations in breast cancer

Liang¹,

Ingalla²,

Yao³

et al. 2022

Sci. Transl. Med.

View full text Add to dashboard Cite

ESR1 (estrogen receptor 1) hotspot mutations are major contributors to therapeutic resistance in estrogen receptor–positive (ER + ) breast cancer. Such mutations confer estrogen independence to ERα, providing a selective advantage in the presence of estrogen-depleting aromatase inhibitors. In addition, ESR1 mutations reduce the potency of tamoxifen and fulvestrant, therapies that bind ERα directly. These limitations, together with additional liabilities, inspired the development of the next generation of ERα-targeted therapeutics, of which giredestrant is a high-potential candidate. Here, we generated Esr1 mutant–expressing mammary gland models and leveraged patient-derived xenografts (PDXs) to investigate the biological properties of the ESR1 mutations and their sensitivity to giredestrant in vivo. In the mouse mammary gland, Esr1 mutations promote hypersensitivity to progesterone, triggering pregnancy-like tissue remodeling and profoundly elevated proliferation. These effects were driven by an altered progesterone transcriptional response and underpinned by gained sites of ERα-PR (progesterone receptor) cobinding at the promoter regions of pro-proliferation genes. PDX experiments showed that the mutant ERα-PR proliferative program is also relevant in human cancer cells. Giredestrant suppressed the mutant ERα-PR proliferation in the mammary gland more so than the standard-of-care agents, tamoxifen and fulvestrant. Giredestrant was also efficacious against the progesterone-stimulated growth of ESR1 mutant PDX models. In addition, giredestrant demonstrated activity against a molecularly characterized ESR1 mutant tumor from a patient enrolled in a phase 1 clinical trial. Together, these data suggest that mutant ERα can collaborate with PR to drive protumorigenic proliferation but remain sensitive to inhibition by giredestrant.

show abstract

Generalized Additive Mixed Modeling of Longitudinal Tumor Growth Reduces Bias and Improves Decision Making in Translational Oncology

Abstract: are employees of Genentech, Inc., a member of the Roche Group. P. Piatkowski and L. Choniawko are employees of Roche Pharmaceuticals. M. Jakubczak is an employee of Ardigen, Inc. A. Starr is an employee of Insitro, Inc.

Cited by 13 publications

References 45 publications

Distinct resistance mechanisms arise to allosteric vs. ATP-competitive AKT inhibitors

Distinct resistance mechanisms arise to allosteric vs. ATP-competitive AKT inhibitors

Growth‐rate model predicts in vivo tumor response from in vitro data

Giredestrant reverses progesterone hypersensitivity driven by estrogen receptor mutations in breast cancer

Contact Info

Product

Resources

About