Neelima Vidula

Cyclin-Dependent Kinase 4/6 Inhibitors for the Treatment of Breast Cancer: A Review of Preclinical and Clinical Data.

For millions of women, breast cancer remains a potentially life-endangering diagnosis. With advances in research, new therapies targeted to tumor biology are emerging to treat the most common form of this disease. Cyclin-dependent kinase (CDK) 4/6 inhibitors are a new class of therapeutic agents that have the potential to improve the outcomes of patients with hormone receptor-positive (HR(+)) breast cancer. Three CDK 4/6 inhibitors have been investigated for the treatment of HR(+) breast cancer, including palbociclib (PD 0332991), ribociclib (LEE011), and abemaciclib (LY2835219). Palbociclib recently received accelerated Food and Drug Administration approval for the treatment of HR(+) metastatic breast cancer in combination with letrozole, and recent data suggest improved outcome when combined with fulvestrant. In this article, the mechanism of action of CDK 4/6 inhibitors, preclinical studies on their efficacy, ongoing clinical trials in breast cancer, and toxicity profiles are reviewed.

Improving Response to Hormone Therapy in Breast Cancer: New Targets, New Therapeutic Options.

The majority of breast cancer expresses the estrogen and or progesterone receptors (ER and PR). In tumors without concomitant HER2 amplification, hormone therapy is a major treatment option for all disease stages. Resistance to hormonal therapy is associated with disease recurrence and progression. Recent studies have identified a number of resistance mechanisms leading to estrogen-independent growth of hormone receptor-positive (HR+) breast cancer as a result of genetic and epigenetic alterations, which could be exploited as novel therapeutic targets. These include acquired mutations in ER-alpha (ESR1) in response to endocrine deprivation; constitutive activation of cyclin-dependent kinases (CDK) 4 and 6; cross talk between ER and growth factor receptor signaling such as HER family members, fibroblast growth factor receptor (FGFR) pathways, intracellular growth, and survival signals PI3K/Akt/mTOR; and epigenetic modifications by histone deacetylase (HDAC) as well as interactions with tumor microenvironment and host immune response. Inhibitors of these pathways are being developed to improve efficacy of hormonal therapy for treatment of both metastatic and early-stage disease. Two agents are currently approved in the United States for the treatment of metastatic HR+ breast cancer, including the mTOR inhibitor everolimus and the CDK4/6 inhibitor palbociclib. Management of toxicity is a critical aspect of treatment; the primary toxicity of everolimus is stomatitis (treated with topical steroids) and of palbociclib is neutropenia (treated with dose reduction/delay). Many agents are in clinical trials, primarily in combination with hormone therapy; novel combinations are under active investigation.

Ultrasound Accelerated Bone Tissue Engineering Monitored with Magnetic Resonance Microscopy

Tissue engineering has the potential to treat bone loss, but current bone restoration methods, including osteogenesis from mesenchymal stem cells (MSCs), require three to four weeks for bone formation to occur. In this study, we stimulated the formation of engineered bone tissue with low-intensity ultrasound, which has been proven to accelerate bone healing in vivo. One group of engineered bone constructs received ultrasound stimulation 20 minutes per day over a 3-week growth period. We monitored the growth of all the engineered constructs quantitatively and noninvasively using magnetic resonance microscopy (MRM), where the T2 relaxation times of all the constructs were measured, on a weekly basis, using an 11.74 T Bruker spectrometer. Histological and immunocytochemical sections were obtained for all constructs and correlated with the MR results. This study shows that ultrasound can accelerate osteogenesis in vitro for tissue engineered bone, the growth and development of which can be monitored using MRM

Translating the Molecular Message of Triple-Negative Breast Cancer into Targeted Therapy

Triple-negative breast cancer (TNBC) has a poor prognosis with limited treatment options. Genomic analysis of TNBCs offers the opportunity to decode TNBC into biologically relevant subtypes with unique molecular targets. With further research, these findings may be translated into effective targeted therapeutic options. Clin Cancer Res; 21(7); 1511–3. ©2014 AACR. See related article by Burstein et al. p. 1688

Emerging data on improving response to hormone therapy: the role of novel targeted agents

ABSTRACT Introduction: Hormone receptor positive (HR+) breast cancer represents the most common subtype of breast cancer. Metastatic HR+ breast cancer may develop resistance to standard hormone therapies, arising from genomic alterations in the estrogen receptor and/or upregulation of other signal transduction pathways. Areas covered: In this review, we discuss hormone resistance and strategies to overcome it, from the pre-clinical and clinical perspectives. This review includes a discussion of inhibition of the PI3K/AKT/mTOR, CDK 4/6, histone deacetylation, fibroblast growth factor receptor, and immune pathways, based on review of relevant literature. Expert commentary: Several emerging novel therapies to improve the response to hormone therapy are approved or are in development. The most promising agents at present are inhibitors of CDK 4/6 and mTOR, which have already been incorporated into treatment in the advanced stage setting and are under study for early stage disease.

Therapeutic case conference from Northwestern: an elderly gentleman with an unsteady gait.

We provide a Therapeutic Conference from Northwestern based on the case of a 63-year-old man who presented with cerebellar ataxia in the setting of a negative workup for a cerebrovascular event, toxic-metabolic, and infectious etiologies and was ultimately diagnosed with a paraneoplastic syndrome secondary to limited-stage small cell lung cancer. A discussion of the clinical management including diagnostic workup and treatment of cerebellar ataxia paraneoplastic syndrome and limited-stage small cell lung cancer is provided. We also discuss the mechanisms of action of chemotherapy used to treat limited-stage small cell lung cancer and potential side effects associated with these agents.