SWOG S1400C (NCT02154490)—A Phase II Study of Palbociclib for Previously Treated Cell Cycle Gene Alteration–Positive Patients with Stage IV Squamous Cell Lung Cancer (Lung-MAP Substudy)

Edelman, Martin J.; Redman, Mary W.; Albain, Kathy S.; McGary, Eric C.; Rafique, Noman M.; Petro, Daniel P.; Waqar, Saiama N.; Minichiello, Katherine; Miao, Jieling; Papadimitrakopoulou, Vassiliki A.; Kelly, Karen; Gandara, David R.; Herbst, Roy S.

doi:10.1016/j.jtho.2019.06.027

Cited by 69 publications

(52 citation statements)

References 17 publications

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“…Umbrella trials evaluate multiple targeted therapies for one single disease, such as BATTLE-2 study and Lung-MAP study. [9][10][11][12][13] However, these studies mainly focused on genomic targets, and did not take molecular subtyping into consideration in the study design. Platform trials set a platform to evaluate multiple targeted therapies for multiple diseases, mainly focusing on refractory solid tumors and rare tumors, such as IMPACT, I-PREDICT and WINTHER platforms.…”

Section: Introductionmentioning

confidence: 99%

Molecular subtyping and genomic profiling expand precision medicine in refractory metastatic triple-negative breast cancer: the FUTURE trial

et al. 2020

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Triple-negative breast cancer (TNBC) is a highly heterogeneous disease, and molecular subtyping may result in improved diagnostic precision and targeted therapies. Our previous study classified TNBCs into four subtypes with putative therapeutic targets. Here, we conducted the FUTURE trial (ClinicalTrials.gov identifier: NCT03805399), a phase Ib/II subtyping-based and genomic biomarkerguided umbrella trial, to evaluate the efficacy of these targets. Patients with refractory metastatic TNBC were enrolled and stratified by TNBC subtypes and genomic biomarkers, and assigned to one of these seven arms: (A) pyrotinib with capecitabine, (B) androgen receptor inhibitor with CDK4/6 inhibitor, (C) anti PD-1 with nab-paclitaxel, (D) PARP inhibitor included, (E) and (F) anti-VEGFR included, or (G) mTOR inhibitor with nab-paclitaxel. The primary end point was the objective response rate (ORR). We enrolled 69 refractory metastatic TNBC patients with a median of three previous lines of therapy (range, 1-8). Objective response was achieved in 20 (29.0%, 95% confidence interval (CI): 18.7%-41.2%) of the 69 intention-to-treat (ITT) patients. Our results showed that immunotherapy (arm C), in particular, achieved the highest ORR (52.6%, 95% CI: 28.9%-75.6%) in the ITT population. Arm E demonstrated favorable ORR (26.1%, 95% CI: 10.2%-48.4% in the ITT population) but with more high grade (≥ 3) adverse events. Somatic mutations of TOP2A and CD8 immunohistochemical score may have the potential to predict immunotherapy response in the immunomodulatory subtype of TNBC. In conclusion, the phase Ib/II FUTURE trial suggested a new concept for TNBC treatment, demonstrating the clinical benefit of subtyping-based targeted therapy for refractory metastatic TNBC.

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Section: Introductionmentioning

confidence: 99%

Molecular subtyping and genomic profiling expand precision medicine in refractory metastatic triple-negative breast cancer: the FUTURE trial

et al. 2020

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“…This is of particular interest given that pharmacological cell cycle arrest in late G1 was found to be sufficient to rescue arterial-venous specification and maturation in an animal model of dysregulated vascular network formation. These experiments employed the CDK4/6 inhibitor palbocilib that is FDA approved for the treatment of HR-positive, HER2-negative metastatic breast cancer 30,31 , and is currently being investigated for other forms of cancer 32,33,34 . Thus, palbocilib or similar drugs may be beneficial for the treatment of vascular diseases, such as arteriovenous and cerebral cavernous malformations, and they may also have utility for the control arterial-venous identity during the creation of arteriovenous fistulas, coronary artery bypass grafting and vascular procedures.…”

Section: Discussionmentioning

confidence: 99%

Endothelial Cell Cycle State Determines Propensity for Arterial-Venous Fate

Chavkin

Genet

Poulet

et al. 2020

Preprint

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SummaryFormation and maturation of a functional blood vascular system is required for the development and maintenance of all tissues in the body. During the process of blood vessel development, primordial endothelial cells are formed and become specified toward arterial or venous fates to generate a circulatory network that provides nutrients and oxygen to, and removes metabolic waste from, all tissues1-3. Specification of arterial and venous endothelial cells occurs in conjunction with suppression of endothelial cell cycle progression4,5, and endothelial cell hyperproliferation is associated with potentially lethal arterial-venous malformations6. However, the mechanistic role that cell cycle state plays in arterial-venous specification is unknown. Herein, studying retinal vascular development in Fucci2aR reporter mice7, we found that venous and arterial endothelial cells are in distinct cell cycle states during development and in adulthood. That is, venous endothelial cells reside in early G1 state, while arterial endothelial cells reside in late G1 state. Endothelial cells in early vs. late G1 exhibited significant differences in gene expression and activity, especially among BMP/TGF-β signaling components. The early G1 state was found to be essential for BMP4-induced venous specification, whereas late G1 state is essential for TGF-β1-induced arterial specification. In a mouse model of endothelial cell hyperproliferation and disrupted vascular remodeling, pharmacological inhibition of endothelial cell cycle rescues the arterial-venous specification defects. Collectively, our results show that endothelial cell cycle control plays a key role in arterial-venous network formation, and distinct cell cycle states provide distinct windows of opportunity for the molecular induction of arterial vs. venous specification.

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“…There is tremendous excitement about the clinical benefits of these agents. Currently, all three CDK4/6 inhibitors are approved (in combination with aromatase inhibitors) for the treatment of estrogen receptor-positive/HER2-negative metastatic breast cancer [186][187][188][189][190], and many clinical trials using these drugs are in progress for other types of cancer [191][192][193][194][195][196][197].…”

Section: Cdk-targeted Anti-cancer Therapymentioning

confidence: 99%

CDKs in Sarcoma: Mediators of Disease and Emerging Therapeutic Targets

Kohlmeyer

Gordon

Tanas

et al. 2020

IJMS

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Sarcomas represent one of the most challenging tumor types to treat due to their diverse nature and our incomplete understanding of their underlying biology. Recent work suggests cyclin-dependent kinase (CDK) pathway activation is a powerful driver of sarcomagenesis. CDK proteins participate in numerous cellular processes required for normal cell function, but their dysregulation is a hallmark of many pathologies including cancer. The contributions and significance of aberrant CDK activity to sarcoma development, however, is only partly understood. Here, we describe what is known about CDK-related alterations in the most common subtypes of sarcoma and highlight areas that warrant further investigation. As disruptions in CDK pathways appear in most, if not all, subtypes of sarcoma, we discuss the history and value of pharmacologically targeting CDKs to combat these tumors. The goals of this review are to (1) assess the prevalence and importance of CDK pathway alterations in sarcomas, (2) highlight the gap in knowledge for certain CDKs in these tumors, and (3) provide insight into studies focused on CDK inhibition for sarcoma treatment. Overall, growing evidence demonstrates a crucial role for activated CDKs in sarcoma development and as important targets for sarcoma therapy.

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SWOG S1400C (NCT02154490)—A Phase II Study of Palbociclib for Previously Treated Cell Cycle Gene Alteration–Positive Patients with Stage IV Squamous Cell Lung Cancer (Lung-MAP Substudy)

Cited by 69 publications

References 17 publications

Molecular subtyping and genomic profiling expand precision medicine in refractory metastatic triple-negative breast cancer: the FUTURE trial

Molecular subtyping and genomic profiling expand precision medicine in refractory metastatic triple-negative breast cancer: the FUTURE trial

Endothelial Cell Cycle State Determines Propensity for Arterial-Venous Fate

CDKs in Sarcoma: Mediators of Disease and Emerging Therapeutic Targets

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