Oral Estrogen Receptor PROTAC Vepdegestrant (ARV-471) Is Highly Efficacious as Monotherapy and in Combination with CDK4/6 or PI3K/mTOR Pathway Inhibitors in Preclinical ER+ Breast Cancer Models

Article

作者: Digianantonio, Katherine ; Quinn, Connor ; Gordon, Debbie ; Békés, Miklós ; Cadelina, Gregory ; Drulyte, Ieva ; Rousseau, Emma ; Willard, Ryan ; Bookbinder, Mark ; Corradi, John ; Soto, Leofal ; Gedrich, Richard ; Morgan, Alicia ; Taylor, Ian C ; Pannone, Melissa ; Wang, Jing ; Pizzano, Jennifer ; Teh, Jessica ; Houston, John ; Bortolon, Elizabeth ; Flanagan, John J ; Andreoli, Monica ; Wang, Gan ; Ferraro, Caterina ; Langley, David R ; Dong, Hanqing ; Davenport, Kim ; Chen, Xin ; Gough, Sheryl M ; Macaluso, Jennifer

Abstract:

Purpose::

Estrogen receptor (ER) alpha signaling is a known driver of ER-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2−) breast cancer. Combining endocrine therapy (ET) such as fulvestrant with CDK4/6, mTOR, or PI3K inhibitors has become a central strategy in the treatment of ER+ advanced breast cancer. However, suboptimal ER inhibition and resistance resulting from the ESR1 mutation dictates that new therapies are needed.

Experimental Design::

A medicinal chemistry campaign identified vepdegestrant (ARV-471), a selective, orally bioavailable, and potent small molecule PROteolysis-TArgeting Chimera (PROTAC) degrader of ER. We used biochemical and intracellular target engagement assays to demonstrate the mechanism of action of vepdegestrant, and ESR1 wild-type (WT) and mutant ER+ preclinical breast cancer models to demonstrate ER degradation-mediated tumor growth inhibition (TGI).

Results::

Vepdegestrant induced ≥90% degradation of wild-type and mutant ER, inhibited ER-dependent breast cancer cell line proliferation in vitro, and achieved substantial TGI (87%–123%) in MCF7 orthotopic xenograft models, better than those of the ET agent fulvestrant (31%–80% TGI). In the hormone independent (HI) mutant ER Y537S patient-derived xenograft (PDX) breast cancer model ST941/HI, vepdegestrant achieved tumor regression and was similarly efficacious in the ST941/HI/PBR palbociclib-resistant model (102% TGI). Vepdegestrant-induced robust tumor regressions in combination with each of the CDK4/6 inhibitors palbociclib, abemaciclib, and ribociclib; the mTOR inhibitor everolimus; and the PI3K inhibitors alpelisib and inavolisib.

Conclusions::

Vepdegestrant achieved greater ER degradation in vivo compared with fulvestrant, which correlated with improved TGI, suggesting vepdegestrant could be a more effective backbone ET for patients with ER+/HER2− breast cancer.

2024-08-01·BREAST CANCER RESEARCH AND TREATMENT

Disparities in PI3K/mTOR inhibitor use, toxicities, and outcomes among patients with metastatic breast cancer

Article

作者: Wright, Jason D ; Accordino, Melissa K ; DeStephano, David ; Hershman, Dawn L ; Shah, Mansi ; Sathe, Claire

PURPOSE:

Novel agents such as PI3K and mTOR inhibitors (PI3K/mTORi) have expanded treatment options in metastatic breast cancer (MBC). Nevertheless, mortality rates remain disproportionately high for Black patients and patients with lower socioeconomic status. Furthermore, clinical trials for these novel agents lacked diversity, so their toxicity profile in minority populations is uncertain.

METHODS:

We conducted a retrospective analysis of EHR-derived data from the Flatiron Health Database for patients with HR+, HER2- MBC. Multivariable logistic regression was used to evaluate factors associated with PI3K/mTORi use and toxicity outcomes.

RESULTS:

A total of 9169 patients with MBC were included in our analysis, of which 1780 (19.4%) received a PI3K/mTORi. We estimated the conditional total effect of insurance through Medicaid, and found lower odds of use of PI3K/mTORi among patients on Medicaid compared to those with commercial insurance (OR 0.73, 95% CI 0.54-0.99, p = 0.049). Odds of PI3K/mTORi use were higher for patients treated at an academic center (OR 1.28, CI 1.06-1.55, p = 0.01). Modeled as a controlled direct effect, Black/African American (Black/AA) race had no impact on odds of PI3K/mTOR use. Black/AA patients had twice the odds of developing hyperglycemia on PI3K/mTORi compared to White patients (OR 2.02, CI 1.24-3.39, p < 0.01).

CONCLUSION:

This analysis of real-world data suggests that the use of PI3K/mTORi is influenced by socioeconomic factors. We also found racial disparities in toxicity outcomes, with Black/AA patients having twice the risk of hyperglycemia. Our findings call for greater efforts to ensure access to novel treatments and improve their tolerability in diverse populations.

2024-07-01·CANCER TREATMENT REVIEWS

The evolving landscape of metastatic HER2-positive, hormone receptor-positive Breast Cancer

Review

作者: Marra, Antonio ; Prat, Aleix ; Burstein, Harold J ; Trapani, Dario ; Valenza, Carmine ; Belli, Carmen ; Nicolò, Eleonora ; Guidi, Lorenzo ; Kotteas, Elias ; Fusco, Nicola ; Boscolo Bielo, Luca ; Curigliano, Giuseppe ; Criscitiello, Carmen

Therapeutic agents targeting Human Epidermal Growth Factor Receptor 2 (HER2) demonstrated to positively impact the prognosis of HER2-positive breast cancer. HER2-positive breast cancer can present either as hormone receptor-negative or positive, defining Triple-positive breast cancer (TPBC). TPBC demonstrate unique gene expression profiles, showing reduced HER2-driven gene expression, as recapitulated by a higher proportion of Luminal-type intrinsic subtypes. The different molecular landscape of TPBC dictates distinctive clinical features, including reduced chemotherapy sensitivity, different patterns of recurrence, and better overall prognosis. Cross-talk between HER2 and hormone receptor signaling seems to be critical to determine resistance to HER2-directed agents. Accordingly, superior outcomes have been achieved with the use of endocrine therapy, representing the first subtype-specific pharmacological intervention unique to this subgroup. Additional targeted agents capable to tackle resistance mechanisms to anti-HER2, hormone agents, or both might further improve the efficacy of treatments, such as PI3K/AKT/mTOR inhibitors, particularly in a biomarker-enriched setting, and CDK4/6-inhibitors, with preliminary data suggesting a role of PAM50 subtyping to predict higher benefits in luminal tumors. Finally, the distinct biology of triple-positive tumors may yield the rationale for considering combinations within antibody-drug conjugate regimens. Accordingly, in this review, we summarized the current evidence and rationale for considering TPBC as a different entity, in which distinct therapeutical approaches leveraging on the different biological profile of TPBC may result in superior anticancer regimens and improved patient-centric outcomes.

项与 PQR-620 相关的新闻（医药）

2023-12-07

·PRNewswire

Leptomeningeal Disease Pipeline Insights: 2023 Analysis Reveals Advancements in Global Cancer Treatment Developments

DUBLIN, Dec. 7, 2023 /PRNewswire/ -- The "Leptomeningeal Disease - Pipeline Insight, 2023" report has been added to ResearchAndMarkets.com's offering. This comprehensive analysis provides an in-depth view of the ongoing developments and future prospects in the therapeutic landscape of Leptomeningeal Disease (LMD), a serious complication that results from cancer cells spreading to the cerebrospinal fluid (CSF). This report is an indispensable resource for anyone interested in the evolving market dynamics and the potential of emerging therapies confronting this challenging medical condition. Unveiling the Scope of Leptomeningeal Disease Research: The report delineates the concerted efforts by pharmaceutical companies and academic researchers who are at the forefront of offering novel solutions to improve the management and therapeutic outcomes of LMD. With a focus on over seven companies and seven pipeline drugs, the document offers a detailed assessment of clinical and nonclinical stage products along with a meticulous analysis of their mechanism of action, clinical studies, and development activities. Emerging Therapies Highlighted: The spotlight is cast on promising candidates like ANG1005 by Angiochem Inc, poised to make a significant impact in LMD treatment. This drug showcases a novel approach by leveraging mechanisms to traverse the blood-brain barrier (BBB)—a profound breakthrough. Moreover, Kazia Therapeutics' Paxalisib represents an innovative PI3K/AKT/mTOR pathway inhibitor in Phase I evaluation, demonstrating the continuous evolution of targeted therapy in this realm. Therapeutic Assessment by Varied Parameters: Detailed Leptomeningeal Disease commercial and clinical assessment. Therapeutics segmentation by product type, developmental stage, route of administration, and molecule type. In-depth analysis of late-stage (Phase III) products. Insights into pipeline development activities and strategic collaborations. The document sets forth a thorough analysis of the pipeline landscape, also evaluating therapies across different stages such as Phase II and I trials. It incorporates a granular examination of the therapies, stratifying them based on administration routes ranging from oral to intrathecal, and classifies them under small molecules, peptides, and other categories. Furthermore, it investigates the intricate details of the product development process, from collaborations, acquisitions, and mergers, to the vital designations granted to drugs in the pipeline. The "Leptomeningeal Disease -Pipeline Insight, 2023" report is a testament to the enduring commitment to equipping industry participants with the knowledge required to navigate the complex terrain of cancer-related central nervous system complications. As the medical community endeavors to improve the prognosis and quality of life for patients afflicted with LMD, such comprehensive research analyses become not just tools for enlightenment, but beacons of hope. For those seeking a thorough understanding of the perspectives and progress in the treatment of Leptomeningeal Disease, this report is an indispensable resource. Interested parties are encouraged to explore the depth of research and analysis presented, shedding light on the future trajectory of therapeutics in this critical field of oncology. Companies profiled in the report include: Angiochem Kazia Therapeutics Mustang Bio Y-mAbs Therapeutics Plus Therapeutics For more information about this report visit About ResearchAndMarkets.com ResearchAndMarkets.com is the world's leading source for international market research reports and market data. We provide you with the latest data on international and regional markets, key industries, the top companies, new products and the latest trends. Media Contact: Research and Markets Laura Wood, Senior Manager [email protected] For E.S.T Office Hours Call +1-917-300-0470 For U.S./CAN Toll Free Call +1-800-526-8630 For GMT Office Hours Call +353-1-416-8900 U.S. Fax: 646-607-1907 Fax (outside U.S.): +353-1-481-1716 Logo: SOURCE Research and Markets

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