Cancer and the Circadian Clock Shafi, Ayesha A; Knudsen, Karen E
Cancer research,
08/2019, Letnik:
79, Številka:
15
Journal Article
Recenzirano
Odprti dostop
The circadian clock is a master regulator of mammalian physiology, regulating daily oscillations of crucial biological processes and behaviors. Notably, circadian disruption has recently been ...identified as an independent risk factor for cancer and classified as a carcinogen. As such, it is imperative to discern the underpinning mechanisms by which circadian disruption alters cancer risk. Emergent data, reviewed herein, demonstrate that circadian regulatory functions play critical roles in several hallmarks of cancer, including control of cell proliferation, cell death, DNA repair, and metabolic alteration. Developing a deeper understanding of circadian-cancer regulation cross-talk holds promise for developing new strategies for cancer interception, prevention, and management.
The majority of estrogen receptor (ER)-positive breast cancers are treated with endocrine therapy. While this is effective, acquired resistance to therapies targeted against ER is a major clinical ...challenge. Here, model systems of ER-positive breast cancers with differential susceptibility to endocrine therapy were employed to define common nodes for new therapeutic interventions. These analyses revealed that cell cycle progression is effectively uncoupled from the activity and functional state of ER in these models. In this context, cyclin D1 expression and retinoblastoma tumor suppressor protein (RB) phosphorylation are maintained even with efficient ablation of ER with pure antagonists. These therapy-resistant models recapitulate a key feature of deregulated RB/E2F transcriptional control. Correspondingly, a gene expression signature of RB-dysfunction is associated with luminal B breast cancer, which exhibits a relatively poor response to endocrine therapy. These collective findings suggest that suppression of cyclin D-supported kinase activity and restoration of RB-mediated transcriptional repression could represent a viable therapeutic option in tumors that fail to respond to hormone-based therapies. Consistent with this hypothesis, a highly selective CDK4/6 inhibitor, PD-0332991, was effective at suppressing the proliferation of all hormone refractory models analyzed. Importantly, PD-0332991 led to a stable cell cycle arrest that was fundamentally distinct from those elicited by ER antagonists, and was capable of inducing aspects of cellular senescence in hormone therapy refractory cell populations. These findings underscore the clinical utility of downstream cytostatic therapies in treating tumors that have experienced failure of endocrine therapy.
Utilization of telehealth as part of the cancer care delivery continuum dramatically escalated in response to the COVID-19 pandemic at major cancer centers across the globe. The rapid shift toward ...telehealth visits for nontreatment cancer care provided immediate benefit through reducing unnecessary risk of exposure, overcoming transportation barriers faced by both patients and caregivers, and fast-tracking care transformation. As such, delineating the impact of telehealth on access, health equity, quality, and outcomes will be essential for refining the use of digital strategies and telehealth toward optimizing cancer care. Herein, experiences to date with telehealth usage for oncology care are reviewed, and priorities are outlined for postpandemic opportunities to improve the lives of patients with cancer through telemedicine.
DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a pleiotropic protein kinase that plays critical roles in cellular processes fundamental to cancer. DNA-PKcs expression and activity are ...frequently deregulated in multiple hematologic and solid tumors and have been tightly linked to poor outcome. Given the potentially influential role of DNA-PKcs in cancer development and progression, therapeutic targeting of this kinase is being tested in preclinical and clinical settings. This review summarizes the latest advances in the field, providing a comprehensive discussion of DNA-PKcs functions in cancer and an update on the clinical assessment of DNA-PK inhibitors in cancer therapy.
Prostate cancer remains a leading cause of cancer death, as there are no durable means to treat advanced disease. Treatment of non-organ-confined prostate cancer hinges on its androgen dependence. ...First-line therapeutic strategies suppress androgen receptor (AR) activity, via androgen ablation and direct AR antagonists, whereas initially effective, incurable, ‘castration-resistant’ tumors arise as a result of resurgent AR activity. Alterations of AR and/or associated regulatory networks are known to restore receptor activity and support resultant therapy-resistant tumor progression. However, recent evidence also reveals an unexpected contribution of the AR ligand, indicating that alterations in pathways controlling androgen synthesis support castration-resistant AR activity. In this report, the mechanisms underlying the lethal pairing of AR deregulation and aberrant androgen synthesis in prostate cancer progression will be discussed.
The DNA-dependent protein kinase (DNA-PK) is a pivotal component of the DNA repair machinery that governs the response to DNA damage, serving to maintain genome integrity. However, the DNA-PK kinase ...component was initially isolated with transcriptional complexes, and recent findings have illuminated the impact of DNA-PK-mediated transcriptional regulation on tumor progression and therapeutic response. DNA-PK expression has also been correlated with poor outcome in selected tumor types, further underscoring the importance of understanding its role in disease. Herein, the molecular and cellular consequences of DNA-PK are considered, with an eye toward discerning the rationale for therapeutic targeting of DNA-PK.
Although DNA-PK is classically considered a component of damage response, recent findings illuminate damage-independent functions of DNA-PK that affect multiple tumor-associated pathways and provide a rationale for the development of novel therapeutic strategies.
Poly (ADP-ribose) polymerase-1 (PARP1) is an abundant, ubiquitously expressed NAD(+)-dependent nuclear enzyme that has prognostic value for a multitude of human cancers. PARP1 activity serves to poly ...(ADP-ribose)-ylate the vast majority of known client proteins and affects a number of cellular and biologic outcomes, by mediating the DNA damage response (DDR), base-excision repair (BER), and DNA strand break (DSB) pathways. PARP1 is also critically important for the maintenance of genomic integrity, as well as chromatin dynamics and transcriptional regulation. Evidence also indicates that PARP-directed therapeutics are "synthetic lethal" in BRCA1/2-deficient model systems. Strikingly, recent studies have unearthed exciting new transcriptional-regulatory roles for PARP1, which has profound implications for human malignancies and will be reviewed herein.
Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors were recently shown to have potential clinical impact in a number of disease settings, particularly as related to cancer therapy, treatment for ...cardiovascular dysfunction, and suppression of inflammation. The molecular basis for PARP1 inhibitor function is complex, and appears to depend on the dual roles of PARP1 in DNA damage repair and transcriptional regulation. Here, the mechanisms by which PARP-1 inhibitors elicit clinical response are discussed, and strategies for translating the preclinical elucidation of PARP-1 function into advances in disease management are reviewed.
Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors were recently shown to have clinical impact in a number of disease settings. In this Perspective, the mechanisms by which PARP1 inhibitors elicit clinical response are discussed, and strategies for translating the preclinical elucidation of PARP1 function into advances in disease management are reviewed.
The retinoblastoma tumour suppressor (RB) is a crucial regulator of cell-cycle progression that is invoked in response to a myriad of anti-mitogenic signals. It has been hypothesized that ...perturbations of the RB pathway confer a synonymous proliferative advantage to tumour cells; however, recent findings demonstrate context-specific outcomes associated with such lesions. Particularly, loss of RB function is associated with differential response to wide-ranging therapeutic agents. Thus, the status of this tumour suppressor may be particularly informative in directing treatment regimens.
Clinical data and models of human disease indicate that androgen receptor (AR) activity is essential for prostate cancer development, growth, and progression. The dependence of prostatic ...adenocarcinoma on AR signaling at all stages of disease has thereby been exploited in the treatment of disseminated tumors, for which ablation of AR function is the goal of first-line therapy. Although these strategies are initially effective, recurrent tumors arise with restored AR activity, and no durable treatment has yet been identified to combat this stage of disease. New insights into AR regulation and the mechanisms underlying resurgent AR activity have provided fertile ground for the development of novel strategies to more effectively inhibit receptor activity and prolong the transition to therapeutic failure.
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