MDM2 Inhibition in Combination with Endocrine Therapy and CDK4/6 Inhibition for the Treatment of ER-Positive Breast Cancer

Portman, Neil; Milioli, Heloisa Helena; Alexandrou, Sarah; Coulson, Rhiannon; Yong, Aliza; Fernandez, Kristine J.; Chia, Karin K.M.; Halilovic, Ensar; Segara, Davendra; Parker, Andrew; Haupt, Sue; Haupt, Ygal; Tilley, Wayne D.; Swarbrick, Alex; Caldon, C. Elizabeth; Lim, Elgene

doi:10.1101/2020.06.09.140921

Cited by 8 publications

(9 citation statements)

References 43 publications

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“…Solid tumor entities as ER‐positive metastatic BC with mdm2 overexpression are also being addressed 47 . Moreover, the inhibition of mdm2 and PD‐1 (pembrolizumab) is being investigated in clinical trials (NCT03611868) and novel therapeutic combinations therapies for ER‐positive BC patients are subject to preclinical studies (anti‐CDK4/6 plus anti‐mdm2) 48 . Remarkably, mdm2 does not only develop TP53‐dependent activity but also can potentiate tumor growth and progression TP53‐independently.…”

Section: Discussionmentioning

confidence: 99%

mdm2 gene amplification is associated with luminal breast cancer progression in humanized PDX mice and a worse outcome of estrogen receptor positive disease

Wege

Rom-Jurek

Jank

et al. 2021

Intl Journal of Cancer

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Estrogen receptor‐positive breast cancer is a highly prevalent but heterogeneous disease among women. Advanced molecular stratification is required to enable individually most efficient treatments based on relevant prognostic and predictive biomarkers. First objective of our study was the hypothesis‐driven discovery of biomarkers involved in tumor progression upon xenotransplantation of Luminal breast cancer into humanized mice. The second objective was the marker validation and correlation with the clinical outcome of Luminal breast cancer disease within the GeparTrio trial. An elevated mdm2 gene copy number was associated with enhanced tumor growth and lung metastasis in humanized tumor mice. The viability, proliferation and migration capacity of inherently mdm2 positive breast cancer cells in vitro were significantly reduced upon mdm2 knockdown or anti‐mdm2 targeting. An mdm2 gain significantly correlated with a worse DFS and OS of Luminal breast cancer patients, albeit it was also associated with an enhanced preoperative pathological response rate. We provide evidence for an enhanced Luminal breast cancer stratification based on mdm2. Moreover, mdm2 can potentially be utilized as a therapeutic target in the Luminal subtype.

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Section: Discussionmentioning

confidence: 99%

mdm2 gene amplification is associated with luminal breast cancer progression in humanized PDX mice and a worse outcome of estrogen receptor positive disease

Wege

Rom-Jurek

Jank

et al. 2021

Intl Journal of Cancer

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“…Similarly, in PALOMA-3, FGFR1 amplification (ctDNA) identified patients at risk of early disease progression [ 54 ].…”

Section: Future Perspectivesmentioning

confidence: 99%

CDK4/6 Inhibitor Treatments in Patients with Hormone Receptor Positive, Her2 Negative Advanced Breast Cancer: Potential Molecular Mechanisms, Clinical Implications and Future Perspectives

Roberto

Astone

Botticelli

et al. 2021

Cancers

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Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer is the most common breast cancer subtype, and endocrine therapy (ET) remains its therapeutic backbone. Although anti-estrogen therapies are usually effective initially, approximately 50% of HR+ patients develop resistance to ET within their lifetime, ultimately leading to disease recurrence and limited clinical benefit. The recent addition of cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (palbociclib, ribociclib, abemaciclib) to ET have remarkably improved the outcome of patients with HR+ advanced breast cancer (ABC) compared with anti-estrogens alone, by targeting the cell-cycle machinery and overcoming some aspects of endocrine resistance. However, which patients are the better candidates for these drugs, which are the main characteristics for a better selection of patients or if there are predictive biomarkers of response, is still unknown. In this review we reported the mechanism of action of CDK4/6 inhibitors as well as their potential mechanism of resistance, their implications in clinical practice and the forthcoming strategies to enhance their efficacy in improving survival and quality of life of patients affected with HR+, HER2−, ABC.

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“…Resistant cells can bypass the G1/S blockade and alter G2/M cell cycle proteins to survive (O’Leary et al, 2018; Pancholi et al, 2020; Fallah et al, 2021; Ono et al, 2021). Therefore, targeting of multiple cell cycle phases may be needed to avoid development of resistance to current therapies in ER+ breast cancer (Aarts et al, 2012; Kettner et al, 2019; Portman et al, 2020; Pandey et al, 2022). Finally, we recognize that work in cell lines may not directly translate to animals and humans, but hope that it may provide insights that can benefit work closer to the clinic.…”

Section: Discussionmentioning

confidence: 99%

Modeling Breast Cancer Proliferation, Drug Synergies, and Alternating Therapies

Demas

Shajahan-Haq

et al. 2022

Preprint

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Estrogen receptor positive (ER+) breast cancer is responsive to a number of targeted therapies used clinically. Unfortunately, the continuous application of targeted therapy often results in resistance. Mathematical modeling of the dynamics of cancer cell drug responses can help find better therapies that not only hold proliferation in check but also potentially stave off resistance. Toward this end, we developed a mathematical model that can simulate various mono, combination and alternating therapies for ER+ breast cancer cells at different doses over long time scales. The model is used to look for optimal drug combinations and predicts a significant synergism between Cdk4/6 inhibitors in combination with the anti-estrogen fulvestrant, which may help explain the clinical success of adding CDK4/6 inhibitors to anti-estrogen therapy. Lastly, the model is used to optimize an alternating treatment protocol that works as well as monotherapy while using less total drug dose.

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MDM2 Inhibition in Combination with Endocrine Therapy and CDK4/6 Inhibition for the Treatment of ER-Positive Breast Cancer

Abstract: 1 Background: Resistance to endocrine therapy is a major clinical challenge in the management of

Cited by 8 publications

References 43 publications

mdm2 gene amplification is associated with luminal breast cancer progression in humanized PDX mice and a worse outcome of estrogen receptor positive disease

mdm2 gene amplification is associated with luminal breast cancer progression in humanized PDX mice and a worse outcome of estrogen receptor positive disease

CDK4/6 Inhibitor Treatments in Patients with Hormone Receptor Positive, Her2 Negative Advanced Breast Cancer: Potential Molecular Mechanisms, Clinical Implications and Future Perspectives

Modeling Breast Cancer Proliferation, Drug Synergies, and Alternating Therapies

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