Inhibiting CDK in Cancer Therapy: Current Evidence and Future Directions

Abstract

Cell cycle dysregulation is a hallmark of all cancers, resulting in uncontrolled proliferation. Cyclin dependent kinases (CDKs), a family of proteins that are involved in the regulation of the cell cycle, are frequently overexpressed or mutated in cancer. Hence, CDK-inhibiting drugs have been developed and evaluated as cancer therapeutics. Clinical trials have shown CDK4/6 inhibitors (CDK4/6i) to be relatively safe and effective, and these are now standard of care treatment for advanced hormone receptor positive breast cancer. Some CDK4/6i drugs are also able to cross the blood brain barrier and may, therefore, offer effective therapy for primary and metastatic central nervous system malignancies. Ongoing research is also evaluating CDK4/6i for additional breast cancer subtypes and non-breast malignancies with promising early phase clinical trial results. Finally, pre-clinical research has identified potential biomarkers for CDK4/6i efficacy and is exploring potential resistance mechanisms to this treatment. Further clinical-translational research is needed to advance patient selection and combinatorial treatment strategies with CDK4/6i in breast cancer and other malignancies.

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Correlation of sociodemographic and clinical parameters with depression and distress in patients with hematologic malignancies

Abstract

A quarter of cancer patients struggle with distress or depression during their illness. Multiple organizations including the National Comprehensive Cancer Network recommend universal screening for distress and depression. Herein, we describe a universal screening program in patients with hematologic malignancies and factors associated with distress and depression. Between December 2013 and February 2015, patients with hematologic malignancies took the Patient Health Questionnaire 9 (PHQ-9) and Distress Thermometer (DT) prior to receiving their first outpatient parenteral chemotherapy. Patient demographic information as well as information regarding visit burden and baseline use of psychiatric medications were recorded. A PHQ-9 score of ≥ 9 and a DT score ≥ 4 suggested a high risk of major depression and distress. Intergroup comparisons of categorical and continuous variables were performed via chi-square and Wilcoxon rank-sum tests. Multivariate models were constructed using the stepwise selection technique using all potential variables. Two hundred forty-six patients with a median age at diagnosis 65 years (range 18–94 years) were included. In the multivariate analysis, a PHQ-9 score ≥ 9 was associated with living alone (P = 0.007), positive PHQ-2 (P = 0.003), and high Charlson comorbidity index (CCI; P = 0.02), while a DT score ≥ 4 was associated with being married (P = 0.03) and female (P = 0.03). There was no other association with high scores on either questionnaire. Patients with hematologic malignancies often have prolonged treatment and surveillance. We identified subpopulations within this group who may be at high risk of developing distress and depression and who should be aggressively screened even when universal screening programs are not available.

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Primary prophylaxis of invasive fungal infections in patients with haematological malignancies: 2017 update of the recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO)

Abstract

Immunocompromised patients are at high risk of invasive fungal infections (IFI), in particular those with haematological malignancies undergoing remission-induction chemotherapy for acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) and recipients of allogeneic haematopoietic stem cell transplants (HSCT). Despite the development of new treatment options in the past decades, IFI remains a concern due to substantial morbidity and mortality in these patient populations. In addition, the increasing use of new immune modulating drugs in cancer therapy has opened an entirely new spectrum of at risk periods. Since the last edition of antifungal prophylaxis recommendations of the German Society for Haematology and Medical Oncology in 2014, seven clinical trials regarding antifungal prophylaxis in patients with haematological malignancies have been published, comprising 1227 patients. This update assesses the impact of this additional evidence and effective revisions. Our key recommendations are the following: prophylaxis should be performed with posaconazole delayed release tablets during remission induction chemotherapy for AML and MDS (AI). Posaconazole iv can be used when the oral route is contraindicated or not feasible. Intravenous liposomal amphotericin B did not significantly decrease IFI rates in acute lymphoblastic leukaemia (ALL) patients during induction chemotherapy, and there is poor evidence to recommend it for prophylaxis in these patients (CI). Despite substantial risk of IFI, we cannot provide a stronger recommendation for these patients. There is poor evidence regarding voriconazole prophylaxis in patients with neutropenia (CII). Therapeutic drug monitoring TDM should be performed within 2 to 5 days of initiating voriconazole prophylaxis and should be repeated in case of suspicious adverse events or of dose changes of interacting drugs (BIItu). General TDM during posaconazole prophylaxis is not recommended (CIItu), but may be helpful in cases of clinical failure such as breakthrough IFI for verification of compliance or absorption.

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Impact of aristolochic acid exposure on oncologic outcomes of upper tract urothelial carcinoma after radical nephroureterectomy

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A2B adenosine receptor agonist induces cell cycle arrest and apoptosis in breast cancer stem cells via ERK1/2 phosphorylation

Abstract

Purpose

It has been reported that cancer stem cells (CSCs) may play a crucial role in the development, recurrence and metastasis of breast cancer. Targeting signaling pathways in CSCs is considered to be a promising strategy for the treatment of cancer. Here, we investigated the role of the A2B adenosine receptor (A2BAR) and its associated signaling pathways in governing the proliferation and viability of breast cancer cell line derived CSCs.

Methods

CSCs were isolated from the breast cancer cell lines MCF-7 and MDA-MB-231 using a mammosphere assay. The effect of the A2BAR agonist BAY606583 on cell proliferation was evaluated using XTT and mammosphere formation assays, respectively. Apoptosis was assessed using Annexin-V staining and cell cycle analyses were performed using flow cytometry. The expression levels of Bax, Bcl-2, cyclin-D1, CDK-4 and (phosphorylated) ERK1/2 were assessed using Western blotting.

Results

Our data revealed that the breast cancer cell line derived mammospheres were enriched for CSCs. We also found that A2BAR stimulation with its agonist BAY606583 inhibited mammosphere formation and CSC viability. In addition, we found that the application of BAY606583 led to CSC cell cycle arrest and apoptosis through the cyclin-D1/Cdk-4 and Bax/Bcl-2 pathways, respectively. Notably, we found that BAY606583 significantly down-regulated ERK1/2 phosphorylation in the breast cancer cell line derived CSCs.

Conclusions

From our results we conclude that A2BAR induces breast CSC cell cycle arrest and apoptosis through downregulation of the ERK1/2 cascade. As such, A2BAR may be considered as a novel target for the treatment of breast cancer.

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Differential Diagnosis of Pancreatic Epidermoid Cyst Without a Solid Component (Residual Splenic Tissue) vs. Mucinous Cystic Neoplasm

Abstract

Purpose

The purpose of this study was to clarify whether there are differences in imaging findings between pancreatic epidermoid cyst (EDC) without a solid component (residual splenic tissue) and mucinous cystic neoplasm (MCN).

Materials and Methods

The study group consisted of histologically proven EDC (eight cases) and MCN (20 cases). CT and MRI findings were compared on the following imaging findings: the shape of the cystic lesions and the presence or absence of septum, calcification, and high-intensity fluid on T1- and diffusion-weighted images (b factor = 1000). The degree of contact with the pancreatic tail was compared between the EDCs and six of the MCNs at the edge of the pancreatic tail.

Results

The EDCs were round (n = 3) or oval (n = 5), while the MCNs consisted of three round, five oval, six pear-like, and six multilobulated lesions (P < 0.05). Septum was present in 4 of 8 (50%) EDCs and 19 of 20 (95%) MCNs (P < 0.05). The presence of calcification (2 of 8 [25%] EDCs vs. 8 of 20 [40%] MCNs), high-intensity fluid on T1-weighted images (2 of 7 [29%] EDCs vs. 5 of 20 [25%] MCNs), and high-intensity fluid on diffusion-weighted images (5 of 7 [71%] EDCs vs. 5 of 20 [25%] MCNs) were not significantly different. The degree of contact with the pancreatic parenchyma was similar between the two types of lesions.

Conclusion

Although the imaging findings for EDC without a solid component and MCN overlap, a pear-like or multilobulated shape may favor a diagnosis of MCN.

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Differential Diagnosis of Pancreatic Epidermoid Cyst Without a Solid Component (Residual Splenic Tissue) vs. Mucinous Cystic Neoplasm

Abstract

Purpose

The purpose of this study was to clarify whether there are differences in imaging findings between pancreatic epidermoid cyst (EDC) without a solid component (residual splenic tissue) and mucinous cystic neoplasm (MCN).

Materials and Methods

The study group consisted of histologically proven EDC (eight cases) and MCN (20 cases). CT and MRI findings were compared on the following imaging findings: the shape of the cystic lesions and the presence or absence of septum, calcification, and high-intensity fluid on T1- and diffusion-weighted images (b factor = 1000). The degree of contact with the pancreatic tail was compared between the EDCs and six of the MCNs at the edge of the pancreatic tail.

Results

The EDCs were round (n = 3) or oval (n = 5), while the MCNs consisted of three round, five oval, six pear-like, and six multilobulated lesions (P < 0.05). Septum was present in 4 of 8 (50%) EDCs and 19 of 20 (95%) MCNs (P < 0.05). The presence of calcification (2 of 8 [25%] EDCs vs. 8 of 20 [40%] MCNs), high-intensity fluid on T1-weighted images (2 of 7 [29%] EDCs vs. 5 of 20 [25%] MCNs), and high-intensity fluid on diffusion-weighted images (5 of 7 [71%] EDCs vs. 5 of 20 [25%] MCNs) were not significantly different. The degree of contact with the pancreatic parenchyma was similar between the two types of lesions.

Conclusion

Although the imaging findings for EDC without a solid component and MCN overlap, a pear-like or multilobulated shape may favor a diagnosis of MCN.

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