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Article ; Online: Seize the engine: Emerging cell cycle targets in breast cancer.

Fuentes-Antrás, Jesús / Bedard, Philippe L / Cescon, David W

2023 Volume 14, Issue 1, Page(s) e1544

Abstract: Breast cancer arises from a series of molecular alterations that disrupt cell cycle checkpoints, leading to aberrant cell proliferation and genomic instability. Targeted pharmacological inhibition of cell cycle regulators has long been considered a ... ...

Abstract	Breast cancer arises from a series of molecular alterations that disrupt cell cycle checkpoints, leading to aberrant cell proliferation and genomic instability. Targeted pharmacological inhibition of cell cycle regulators has long been considered a promising anti-cancer strategy. Initial attempts to drug critical cell cycle drivers were hampered by poor selectivity, modest efficacy and haematological toxicity. Advances in our understanding of the molecular basis of cell cycle disruption and the mechanisms of resistance to CDK4/6 inhibitors have reignited interest in blocking specific components of the cell cycle machinery, such as CDK2, CDK4, CDK7, PLK4, WEE1, PKMYT1, AURKA and TTK. These targets play critical roles in regulating quiescence, DNA replication and chromosome segregation. Extensive preclinical data support their potential to overcome CDK4/6 inhibitor resistance, induce synthetic lethality or sensitise tumours to immune checkpoint inhibitors. This review provides a biological and drug development perspective on emerging cell cycle targets and novel inhibitors, many of which exhibit favourable safety profiles and promising activity in clinical trials.
MeSH term(s)	Cell Cycle ; Cell Division ; Cell Proliferation ; Aurora Kinase A ; Cyclin-Dependent Kinase Inhibitor Proteins ; Neoplasms
Chemical Substances	Aurora Kinase A (EC 2.7.11.1) ; Cyclin-Dependent Kinase Inhibitor Proteins
Language	English
Publishing date	2023-12-21
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2697013-2
ISSN	2001-1326 ; 2001-1326
ISSN (online)	2001-1326
ISSN	2001-1326
DOI	10.1002/ctm2.1544
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Accelerating drug access from advanced to early breast cancer: the special case of oral selective estrogen receptor degraders.

Wilson, Brooke E / Cescon, David W

Current opinion in oncology

2021 Volume 33, Issue 6, Page(s) 538–546

Abstract: Purpose of review: For hormone receptor positive breast cancer, the development of endocrine resistance commonly occurs, presenting as either disease progression in the metastatic setting or recurrence during or following adjuvant endocrine therapy. ... ...

Abstract	Purpose of review: For hormone receptor positive breast cancer, the development of endocrine resistance commonly occurs, presenting as either disease progression in the metastatic setting or recurrence during or following adjuvant endocrine therapy. Various mechanisms of resistance have been described. In order to reduce or overcome endocrine resistance, there has been substantial interest in developing potent and orally bioavailable selective estrogen receptor degraders (SERDs) for metastatic disease and select patients with early-stage estrogen receptor positive breast cancer. Recent findings: At least 11 oral SERDs have entered clinical development. We review current studies in both the metastatic and neoadjuvant/adjuvant setting and present the available evidence of benefit and toxicity for these novel agents. Further characterization of changes to tissue-based biomarkers such as estrogen receptor, progesterone receptor and Ki67 expression and blood-based biomarkers such as ctDNA and estrogen receptor 1 mutation may help to refine therapeutic strategies, combinations, and patient selection to identify women who are most likely to benefit from these novel endocrine agents. Summary: Although SERDs have clear therapeutic potential based on nonclinical studies and have demonstrated early signs of activity in phase I and II studies in the metastatic setting, ongoing research is needed to clarify when and in whom these agents may have greatest clinical benefit.
MeSH term(s)	Antineoplastic Agents, Hormonal/administration & dosage ; Breast Neoplasms/drug therapy ; Breast Neoplasms/metabolism ; Clinical Trials, Phase II as Topic ; Female ; Humans ; Randomized Controlled Trials as Topic ; Receptors, Estrogen/metabolism ; Selective Estrogen Receptor Modulators/administration & dosage
Chemical Substances	Antineoplastic Agents, Hormonal ; Receptors, Estrogen ; Selective Estrogen Receptor Modulators
Language	English
Publishing date	2021-09-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1049384-0
ISSN	1531-703X ; 1040-8746
ISSN (online)	1531-703X
ISSN	1040-8746
DOI	10.1097/CCO.0000000000000786
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Zs.A 3046: Show issues

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Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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Jg. 1995 - 2021: Lesesall (2.OG)
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Article ; Online: Pembrolizumab monotherapy in metastatic triple-negative breast cancer.

Amir, Eitan / Cescon, David W

The Lancet. Oncology

2021 Volume 22, Issue 4, Page(s) 415–417

MeSH term(s)	Antibodies, Monoclonal, Humanized ; Humans ; Neoadjuvant Therapy ; Triple Negative Breast Neoplasms
Chemical Substances	Antibodies, Monoclonal, Humanized ; pembrolizumab (DPT0O3T46P)
Language	English
Publishing date	2021-03-04
Publishing country	England
Document type	Journal Article
ZDB-ID	2049730-1
ISSN	1474-5488 ; 1470-2045
ISSN (online)	1474-5488
ISSN	1470-2045
DOI	10.1016/S1470-2045(21)00019-X
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Zs.A 5696: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 460: Show issues

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Article ; Online: Development of novel agents for the treatment of early estrogen receptor positive breast cancer.

Elliott, Mitchell J / Cescon, David W

Breast (Edinburgh, Scotland)

2021 Volume 62 Suppl 1, Page(s) S34–S42

Abstract: Estrogen receptor (ER+) breast cancer is the most frequently diagnosed breast cancer subtype. Currently, adjuvant treatment for early stage disease consists of endocrine therapy, with or without chemotherapy and bone-targeted therapy, delivered in a risk- ...

Abstract	Estrogen receptor (ER+) breast cancer is the most frequently diagnosed breast cancer subtype. Currently, adjuvant treatment for early stage disease consists of endocrine therapy, with or without chemotherapy and bone-targeted therapy, delivered in a risk-adapted manner. Despite this multimodal approach, a significant proportion of high risk patients will develop incurable distant recurrences. There is an ongoing need to develop new treatment strategies that address the biologic causes of treatment failure and to identify the individual patients who can benefit from such interventions. Here we review the clinical investigation of targeted and novel therapies, including inhibitors of the PI3K-AKT-mTOR pathway, oral selective estrogen receptor degraders (SERDs), and PARP-inhibitors for the treatment of early ER+ breast cancer. Furthermore, we highlight opportunities in biomarker development to help guide the delivery of escalated adjuvant strategies.
MeSH term(s)	Breast Neoplasms/drug therapy ; Breast Neoplasms/metabolism ; Estrogen Antagonists ; Female ; Humans ; Phosphatidylinositol 3-Kinases ; Receptors, Estrogen/metabolism ; Selective Estrogen Receptor Modulators/therapeutic use
Chemical Substances	Estrogen Antagonists ; Receptors, Estrogen ; Selective Estrogen Receptor Modulators
Language	English
Publishing date	2021-11-16
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	1143210-x
ISSN	1532-3080 ; 0960-9776
ISSN (online)	1532-3080
ISSN	0960-9776
DOI	10.1016/j.breast.2021.11.007
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Zs.A 3620: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 588: Show issues

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Article ; Online: PLK4 as a potential target to enhance radiosensitivity in triple-negative breast cancer.

Pellizzari, Sierra / Bhat, Vasudeva / Athwal, Harjot / Cescon, David W / Allan, Alison L / Parsyan, Armen

Radiation oncology (London, England)

2024 Volume 19, Issue 1, Page(s) 24

Abstract: Radioresistance is one of the barriers to developing more effective therapies against the most aggressive, triple-negative, breast cancer (TNBC) subtype. In our previous studies, we showed that inhibition of Polo-like Kinase 4 (PLK4) by a novel drug, CFI- ...

Abstract	Radioresistance is one of the barriers to developing more effective therapies against the most aggressive, triple-negative, breast cancer (TNBC) subtype. In our previous studies, we showed that inhibition of Polo-like Kinase 4 (PLK4) by a novel drug, CFI-400945 significantly enhances the anticancer effects of radiotherapy (RT) compared to single treatment alone. Here we further investigate the role of PLK4 in enhancing radiation effects in TNBC and explore mechanisms of PLK4 inhibition and radiation combinatorial antiproliferative effects. To assess cellular proliferation in response to treatments, we used colony formation assays in TNBC cell lines and patient-derived organoids (PDOs). Downregulation of PLK4 expression was achieved using siRNA silencing in TNBC cell lines. Immunofluorescence against centrin was used to assess the alteration of centriole amplification in response to treatments. We observed that inhibition of PLK4 by CFI-400945 or Centrinone B or its downregulation by siRNA, when combined with RT, resulted in a significant increase in antiproliferative effect in TNBC cells lines and PDOs compared to untreated or single-treated cells. Anticancer synergy was observed using a response matrix in PDOs treated with CFI-400945 and RT. We show that the overamplification of centrioles might be involved in the combined antiproliferative action of RT and PLK4 inhibition. Our data suggest that PLK4 is a promising target for enhancing the anticancer effects of RT in TNBC that, at least in part, is modulated by the overamplification of centrioles. These results support further mechanistic and translational studies of anti-PLK4 agents and RT as an anticancer combination treatment strategy.
MeSH term(s)	Humans ; Triple Negative Breast Neoplasms/genetics ; Triple Negative Breast Neoplasms/radiotherapy ; Cell Line, Tumor ; Cell Proliferation ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism ; RNA, Small Interfering/pharmacology ; Radiation Tolerance ; Protein Serine-Threonine Kinases
Chemical Substances	RNA, Small Interfering ; PLK4 protein, human (EC 2.7.1.-) ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2024-02-16
Publishing country	England
Document type	Journal Article
ZDB-ID	2224965-5
ISSN	1748-717X ; 1748-717X
ISSN (online)	1748-717X
ISSN	1748-717X
DOI	10.1186/s13014-024-02410-z
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Article: Exploring immune interactions in triple negative breast cancer: IL-1β inhibition and its therapeutic potential.

Wilson, Brooke E / Shen, Qiang / Cescon, David W / Reedijk, Michael

Frontiers in genetics

2023 Volume 14, Page(s) 1086163

Abstract: Triple negative breast cancer (TNBC) has poor prognosis when compared to other breast cancer subtypes. Despite pre-clinical data supporting an immune targeted approach for TNBCs, immunotherapy has failed to demonstrate the impressive responses seen in ... ...

Abstract	Triple negative breast cancer (TNBC) has poor prognosis when compared to other breast cancer subtypes. Despite pre-clinical data supporting an immune targeted approach for TNBCs, immunotherapy has failed to demonstrate the impressive responses seen in other solid tumor malignancies. Additional strategies to modify the tumor immune microenvironment and potentiate response to immunotherapy are needed. In this review, we summarise phase III data supporting the use of immunotherapy for TNBC. We discuss the role of IL-1β in tumorigenesis and summarize pre-clinical data supporting IL-1β inhibition as a potential therapeutic strategy in TNBC. Finally, we present current trials evaluating IL-1β in breast cancer and other solid tumor malignancies and discuss future studies that may provide a strong scientific rationale for the combination of IL-1β and immunotherapy in the neoadjuvant and metastatic setting for people with TNBC.
Language	English
Publishing date	2023-03-29
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2023.1086163
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Article ; Online: Can a Late Interception by Circulating Tumor DNA Deliver a Win in Estrogen Receptor-Positive Early Breast Cancer?

Cescon, David W / Kalinsky, Kevin / DeMichele, Angela M

Journal of clinical oncology : official journal of the American Society of Clinical Oncology

2022 Volume 40, Issue 22, Page(s) 2395–2397

MeSH term(s)	Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Circulating Tumor DNA/genetics ; Female ; Humans ; Prognosis ; Receptor, ErbB-2 ; Receptors, Estrogen/genetics
Chemical Substances	Circulating Tumor DNA ; Receptors, Estrogen ; Receptor, ErbB-2 (EC 2.7.10.1)
Language	English
Publishing date	2022-06-04
Publishing country	United States
Document type	Editorial ; Comment
ZDB-ID	604914-x
ISSN	1527-7755 ; 0732-183X
ISSN (online)	1527-7755
ISSN	0732-183X
DOI	10.1200/JCO.22.01026
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Zs.A 1847: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 650: Show issues

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Article ; Online: Liquid biopsies to predict CDK4/6 inhibitor efficacy and resistance in breast cancer.

Main, Sasha C / Cescon, David W / Bratman, Scott V

Cancer drug resistance (Alhambra, Calif.)

2022 Volume 5, Issue 3, Page(s) 727–748

Abstract: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors combined with endocrine therapy have transformed the treatment of estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer. However, some ... ...

Abstract	Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors combined with endocrine therapy have transformed the treatment of estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer. However, some patients do not respond to this treatment, and patients inevitably develop resistance, such that novel biomarkers are needed to predict primary resistance, monitor treatment response for acquired resistance, and personalize treatment strategies. Circumventing the spatial and temporal limitations of tissue biopsy, newly developed liquid biopsy approaches have the potential to uncover biomarkers that can predict CDK4/6 inhibitor efficacy and resistance in breast cancer patients through a simple blood test. Studies on circulating tumor DNA (ctDNA)-based liquid biopsy biomarkers of CDK4/6 inhibitor resistance have focused primarily on genomic alterations and have failed thus far to identify clear and clinically validated predictive biomarkers, but emerging epigenetic ctDNA methodologies hold promise for further discovery. The present review outlines recent advances and future directions in ctDNA-based biomarkers of CDK4/6 inhibitor treatment response.
Language	English
Publishing date	2022-06-22
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2578-532X
ISSN (online)	2578-532X
DOI	10.20517/cdr.2022.37
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Article: The Clinical, Genomic, and Transcriptomic Landscape of BRAF Mutant Cancers.

Kazandjian, Suzanne / Rousselle, Emmanuelle / Dankner, Matthew / Cescon, David W / Spreafico, Anna / Ma, Kim / Kavan, Petr / Batist, Gerald / Rose, April A N

Cancers

2024 Volume 16, Issue 2

Abstract: Background: BRAF mutations are classified into four molecularly distinct groups, and Class 1 (V600) mutant tumors are treated with targeted therapies. Effective treatment has not been established for Class 2/3 or BRAF Fusions. We investigated whether ... ...

Abstract	Background: BRAF mutations are classified into four molecularly distinct groups, and Class 1 (V600) mutant tumors are treated with targeted therapies. Effective treatment has not been established for Class 2/3 or BRAF Fusions. We investigated whether BRAF mutation class differed according to clinical, genomic, and transcriptomic variables in cancer patients. Methods: Using the AACR GENIE (v.12) cancer database, the distribution of BRAF mutation class in adult cancer patients was analyzed according to sex, age, primary race, and tumor type. Genomic alteration data and transcriptomic analysis was performed using The Cancer Genome Atlas. Results: BRAF mutations were identified in 9515 (6.2%) samples among 153,834, with melanoma (31%), CRC (20.7%), and NSCLC (13.9%) being the most frequent cancer types. Class 1 harbored co-mutations outside of the MAPK pathway (TERT, RFN43) vs. Class 2/3 mutations (RAS, NF1). Across all tumor types, Class 2/3 were enriched for alterations in genes involved in UV response and WNT/β-catenin. Pathway analysis revealed enrichment of WNT/β-catenin and Hedgehog signaling in non-V600 mutated CRC. Males had a higher proportion of Class 3 mutations vs. females (17.4% vs. 12.3% q = 0.003). Non-V600 mutations were generally more common in older patients (aged 60+) vs. younger (38% vs. 15% Conclusions: Class 2/3 BRAFs are more present in Black male patients with co-mutations outside of the MAPK pathway, likely requiring additional oncogenic input for tumorigenesis. Improving access to NGS and trial enrollment will help the development of targeted therapies for non-V600 BRAF mutations.
Language	English
Publishing date	2024-01-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers16020445
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Article: Patient-derived cancer models: Valuable platforms for anticancer drug testing.

Genta, Sofia / Coburn, Bryan / Cescon, David W / Spreafico, Anna

Frontiers in oncology

2022 Volume 12, Page(s) 976065

Abstract: Molecularly targeted treatments and immunotherapy are cornerstones in oncology, with demonstrated efficacy across different tumor types. Nevertheless, the overwhelming majority metastatic disease is incurable due to the onset of drug resistance. ... ...

Abstract	Molecularly targeted treatments and immunotherapy are cornerstones in oncology, with demonstrated efficacy across different tumor types. Nevertheless, the overwhelming majority metastatic disease is incurable due to the onset of drug resistance. Preclinical models including genetically engineered mouse models, patient-derived xenografts and two- and three-dimensional cell cultures have emerged as a useful resource to study mechanisms of cancer progression and predict efficacy of anticancer drugs. However, variables including tumor heterogeneity and the complexities of the microenvironment can impair the faithfulness of these platforms. Here, we will discuss advantages and limitations of these preclinical models, their applicability for drug testing and in co-clinical trials and potential strategies to increase their reliability in predicting responsiveness to anticancer medications.
Language	English
Publishing date	2022-08-12
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2022.976065
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