Cyclocreatine Suppresses Creatine Metabolism and Impairs Prostate Cancer Progression.

Prostate cancer is the second most common cause of cancer mortality in men worldwide. Applying a novel genetically engineered mouse model (GEMM) of aggressive prostate cancer driven by deficiency of the tumor suppressors PTEN and Sprouty2 (SPRY2), we identified enhanced creatine metabolism as a central component of progressive disease. Creatine treatment was associated with enhanced cellular basal respiration in vitro and increased tumor cell proliferation in vivo. Stable isotope tracing revealed that intracellular levels of creatine in prostate cancer cells are predominantly dictated by exogenous availability rather than by de novo synthesis from arginine. Genetic silencing of creatine transporter SLC6A8 depleted intracellular creatine levels and reduced the colony-forming capacity of human prostate cancer cells. Accordingly, in vitro treatment of prostate cancer cells with cyclocreatine, a creatine analog, dramatically reduced intracellular levels of creatine and its derivatives phosphocreatine and creatinine and suppressed proliferation. Supplementation with cyclocreatine impaired cancer progression in the PTEN- and SPRY2-deficient prostate cancer GEMMs and in a xenograft liver metastasis model. Collectively, these results identify a metabolic vulnerability in prostate cancer and demonstrate a rational therapeutic strategy to exploit this vulnerability to impede tumor progression. SIGNIFICANCE: Enhanced creatine uptake drives prostate cancer progression and confers a metabolic vulnerability to treatment with the creatine analog cyclocreatine.

The care of older cancer patients in the United Kingdom.

The ageing population poses new challenges globally. Cancer care for older patients is one of these challenges, and it has a significant impact on societies. In the United Kingdom (UK), as the number of older cancer patients increases, the management of this group has become part of daily practice for most oncology teams in every geographical area. Older cancer patients are at a higher risk of both under- and over-treatment. Therefore, the assessment of a patient's biological age and effective organ functional reserve becomes paramount. This may then guide treatment decisions by better estimating a prognosis and the risk-to-benefit ratio of a given therapy to anticipate and mitigate against potential toxicities/difficulties. Moreover, older cancer patients are often affected by geriatric syndromes and other issues that impact their overall health, function and quality of life. Comprehensive geriatric assessments offer an opportunity to identify and address health problems which may then optimise one's fitness and well-being. Whilst it is widely accepted that older cancer patients may benefit from such an approach, resources are often scarce, and access to dedicated services and research remains limited to specific centres across the UK. The aim of this project is to map the current services and projects in the UK to learn from each other and shape the future direction of care of older patients with cancer.

A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours.

PURPOSE: We performed a multi-centre phase I study to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the orally available small molecule mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, WX-554, and to determine the optimal biological dose for subsequent trials. EXPERIMENTAL DESIGN: Patients with treatment-refractory, advanced solid tumours, with adequate performance status and organ function were recruited to a dose-escalation study in a standard 3 + 3 design. The starting dose was 25 mg orally once weekly with toxicity, PK and PD guided dose-escalation with potential to explore alternative schedules. RESULTS: Forty-one patients with advanced solid tumours refractory to standard therapies and with adequate organ function were recruited in eight cohorts up to doses of 150 mg once weekly and 75 mg twice weekly. No dose-limiting toxicities were observed during the study, and a maximum tolerated dose (MTD) was not established. The highest dose cohorts demonstrated sustained inhibition of extracellular signal-regulated kinase (ERK) phosphorylation in peripheral blood mononuclear cells following ex-vivo phorbol 12-myristate 13-acetate stimulation. There was a decrease of 70 ± 26% in mean phosphorylated (p)ERK in C1 day 8 tumour biopsies when compared with pre-treatment tumour levels in the 75 mg twice a week cohort. Prolonged stable disease (>6 months) was seen in two patients, one with cervical cancer and one with ampullary carcinoma. CONCLUSIONS: WX-554 was well tolerated, and an optimal biological dose was established for further investigation in either a once or twice weekly regimens. The recommended phase 2 dose is 75 mg twice weekly.

A community cross-sectional survey of medical problems in 440 children with Down syndrome in New York State.

OBJECTIVE: To determine the frequency of medical problems in a large population of children with Down syndrome. STUDY DESIGN: Study population included 440 children with Down syndrome (ages 3-14 years) identified primarily through the New York Congenital Malformations Registry. Parents completed questionnaires on medical problems. RESULTS: Our study population was predominately White (92.3%), non-Hispanic (72.3%) with at least 1 college educated parent (72.3%). The prevalence of medical problems was as follows: heart disease (55%), hearing problem (39%), vision problem (39%), thyroid disease (27%), celiac disease (5%), alopecia (5%), seizures (7%), asthma/reactive airway disease (32%), diabetes (1%), and juvenile rheumatoid arthritis (0.2%). Of the children with heart disease, 58% needed surgery at a mean age of 9 months. Of the children with hearing loss, 29% were identified on newborn screening and 13% used an amplification device. Of the children with thyroid disease, 31% were diagnosed in the newborn period. Only 7% of these children with Down syndrome had no medical problem listed. CONCLUSION: Prevalence data of medical illnesses in a large population of children with Down syndrome provide us with data to support implementation of the American Academy of Pediatrics guidelines for health supervision for children with Down syndrome. The long-term health implications of the conditions we surveyed will be important for decreasing morbidity and increasing overall health and wellness into adulthood.

Endometrial carcinoma expresses an increased cathepsin B/D ratio.

OBJECTIVES: Cathepsins B and D belong to a family of proteases involved in tumor invasion and metastasis. As such they may function as biomarkers for the aggressiveness of a given tumor. We examined the enzymatic activity of these proteins as well as the cellular and extracellular distribution of cathepsins B and D. METHODS: 39 snap frozen tissue samples were assayed for activity fluorometrically with cathepsin-specific peptide substrates in combination with specific inhibitors. 4 groups were established: benign tissue, stage I/grade 1, stage i/grade 3, and stage IIIC/any grade. IHC staining for cathepsin B with the percentage of counterstained enzyme calculated from each specimen. RESULTS: A significantly increased level of cathepsin B activity was seen in malignant tissue specimens when compared to benign tissue. The cathepsin B/D ratio confirmed and was required to detect the significance of this distinction for each malignant group when compared to benign samples. There were no differences in cathepsin B or D expression detected between the various malignant groups. IHC staining for cathepsin B was more diffuse in the malignant tissues. CONCLUSIONS: Malignant endometrium displays increased cathepsin B activity when compared benign samples. The cathepsin B/D ratio is increased for each of the malignant groups studied when compared directly to benign endometrium. The cathepsin B/D ratio cannot be utilized to distinguish the stage or grade between any of the malignant groups studied. This ratio may serve to distinguish malignant from benign tumor samples and may be a constitutive change in the malignant transformation.

Rate of elimination of Wolbachia pipientis by doxycycline in vitro increases following drug withdrawal.

Wolbachia pipientis is an obligate intracellular bacterium within the family Anaplasmataceae that infects many terrestrial arthropods and arthropod-transmitted nematodes (filariae). Several filarial species are major human pathogens, and antibiotics with activity against Wolbachia offer a promising new therapeutic approach, since the adult worms are relatively refractory to conventional anthelmintics but depend on Wolbachia for reproduction and viability. In a natural filarial parasite of cattle, Onchocerca ochengi, intermittent chemotherapy is adulticidal whereas the equivalent dose administered as a continuous treatment is not. To investigate this further and to aid the design of efficacious regimens for human therapy, we used Wolbachia-infected Aedes albopictus mosquito cells in vitro. Here, we describe for the first time the accelerated depletion of bacteria after antibiotic withdrawal relative to the rate of elimination in the continuous presence of the drug. Mosquito cells were incubated with doxycycline while changes in 16S (bacterial) and 18S (host) rRNA and rRNA genes were determined by quantitative PCR assays. In cultures treated for 7 or 14 days followed by 7 days of drug withdrawal, the Wolbachia-to-Aedes rRNA ratio declined by approximately 6 log, whereas immediately after 14 or 21 days of continuous treatment, the reduction was only approximately 4 log (P < 0.05). However, low levels of 16S rRNA remained after 21 days of treatment, irrespective of whether doxycycline was withdrawn. Application of similar methodology to related intracellular bacteria may reveal that this posttreatment effect is not restricted to Wolbachia and could have wider implications for the design of intermittent regimens for antibiotic chemotherapy.