Barriers to Effective Drug Treatment for Brain Metastases: A Multifactorial Problem in the Delivery of Precision Medicine

The treatment of metastatic lesions in the brain represents a serious unmet medical need in the field of neuro-oncology. Even though many effective compounds have demonstrated success in treating peripheral (non-CNS) tumors with targeted agents, one aspect of this lack of success in the brain may be related to poor delivery of otherwise effective compounds. Many factors can influence the brain delivery of these agents, but one key barrier is a heterogeneously “leaky” BBB that expresses efflux transporters that limit the BBB permeability for many targeted agents. Future success in therapeutics for brain metastases must take into account the adequate delivery of “active, free drug” to the target, and may include combinations of targeted drugs that are appropriate to address each individual patient’s tumor type. This review discusses some issues that are pertinent to precision medicine for brain metastases, using specific examples of tumor types that have a high incidence of brain metastases.     

Meta-chlorophenylpiperazine enhances leptin sensitivity in diet-induced obese mice

Background and Purpose

Most forms of human obesity are characterized by impaired leptin sensitivity and, therefore, the effectiveness of anti-obesity leptin therapy in these leptin-resistant obese patients is marginal. Hence, the development of strategies to increase leptin sensitivity is of high priority in the field of obesity research.

Experimental Approach

We first examined the effects of co-administration of leptin and meta-chlorophenylpiperazine (mCPP), an agonist of 5-HT_2C and 5-HT_1B receptors, on energy balance in leptin-resistant diet-induced obese (DIO) mice. We further assessed leptin-induced phosphorylation of the STAT-3 (pSTAT3) in various brain regions of DIO mice pretreated with mCPP or in mice genetically lacking 5-HT_2C receptors.

Results

Co-administration of mCPP with leptin had an additive effect on reducing body weight in DIO mice. Furthermore, mCPP pretreatment in DIO mice enhanced leptin-induced pSTAT3 in the arcuate nucleus, the ventromedial hypothalamic nucleus, and the ventral premammillary nucleus. Finally, deletion of 5-HT_2C receptors significantly blunted leptin-induced pSTAT3 in these same hypothalamic regions.

Conclusions and Implications

Our study provides evidence that drugs, which activate 5-HT_2C receptors, could function as leptin sensitizers and be used in combination with leptin to provide additional weight loss in DIO.Tables of Links

Prostatic evaluation by transrectal sonography with histopathologic correlation: the echopenic appearance of early carcinoma

Fifty-two patients with clinical stage A and B carcinomas of the prostate were imaged by ultrasound (US) transrectally with a 5-MHz linear array transducer and transabdominally with a 3-MHz sector scanner prior to radical prostatectomy. The fresh specimens of 44 prostate glands were scanned in a water bath with a 5-MHz linear array transducer in multiple planes. In all cases, histopathologic correlation was obtained. Prostatic carcinoma presented as an echopenic lesion in 54% of the specimens, as a slightly hypoechoic area in 22%, and could not be identified in 24% because of its isoechoic characteristics. In contrast to many previous reports, no instance of echogenic cancer was observed.     

Role of perfusion pressure and flow in major organ dysfunction after cardiopulmonary bypass

The role of perfusion pressure and flow during cardiopulmonary bypass with moderate hypothermia and hemodilution in the development of new postoperative renal or clinically apparent cerebral dysfunction was examined in 504 adults. Cardiopulmonary bypass flow was targeted at greater than 40 mL.kg-1.min-1 and pressure at greater than 50 mm Hg. Flows and pressures less than target occurred in 21.6% and 97.1% of patients, respectively. Fifteen patients (3.0%) suffered new renal and 13 (2.6%) new central nervous system dysfunction. Low pressure or flow during cardiopulmonary bypass, expressed in absolute values or in intensity-duration units, were not predictors of either adverse outcome. Multivariate analysis identified use of postoperative intraaortic balloon counterpulsation (p less than 10(-6], excessive blood loss in the ICU (p less than 10(-4], need for vasopressors before cardiopulmonary bypass (p less than 10(-4], postoperative myocardial infarction (p less than 10(-3], emergency reoperation (p less than 0.002), excessive postoperative transfusion (p less than 0.02), and chronic renal disease (p less than 0.03) as independent predictors of postoperative renal dysfunction. Independent predictors of postoperative central nervous system dysfunction were cardiopulmonary resuscitation in the intensive care unit (p less than 10(-6], intracardiac thrombus or valve calcification (p less than 0.02), and chronic renal disease (p less than 0.03). Age greater than 65 years (40.7% of patients) did not predict either outcome. We conclude that failure of the native circulation during periods other than cardiopulmonary bypass rather than the flows and pressures considered here is the major cause of renal and clinically apparent central nervous system dysfunction after cardiac operations.     

Transgenic amplification of glucocorticoid action in adipose tissue causes high blood pressure in mice

Obesity is closely associated with the metabolic syndrome, a combination of disorders including insulin resistance, diabetes, dyslipidemia, and hypertension. A role for local glucocorticoid reamplification in obesity and the metabolic syndrome has been suggested. The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) regenerates active cortisol from inactive 11-keto forms, and aP2-HSD1 mice with relative transgenic overexpression of this enzyme in fat cells develop visceral obesity with insulin resistance and dyslipidemia. Here we report that aP2-HSD1 mice also have high arterial blood pressure (BP). The mice have increased sensitivity to dietary salt and increased plasma levels of angiotensinogen, angiotensin II, and aldosterone. This hypertension is abolished by selective angiotensin II receptor AT-1 antagonist at a low dose that does not affect BP in non-Tg littermates. These findings suggest that activation of the circulating renin-angiotensin system (RAS) develops in aP2-HSD1 mice. The long-term hypertension is further reflected by an appreciable hypertrophy and hyperplasia of the distal tubule epithelium of the nephron, resembling salt-sensitive or angiotensin II-mediated hypertension. Taken together, our findings suggest that overexpression of 11beta-HSD1 in fat is sufficient to cause salt-sensitive hypertension mediated by an activated RAS. The potential role of adipose 11beta-HSD1 in mediating critical features of the metabolic syndrome extends beyond obesity and metabolic complications to include the most central cardiovascular feature of this disorder.     

Mice lacking ghrelin receptors resist the development of diet-induced obesity

Ghrelin is the endogenous ligand for the growth hormone secretagogue receptor (GHSR; ghrelin receptor). Since its discovery, accumulating evidence has suggested that ghrelin may play a role in signaling and reversing states of energy insufficiency. For example, ghrelin levels rise following food deprivation, and ghrelin administration stimulates feeding and increases body weight and adiposity. However, recent loss-of-function studies have raised questions regarding the physiological significance of ghrelin in regulating these processes. Here, we present results of a study using a novel GHSR-null mouse model, in which ghrelin administration fails to acutely stimulate food intake or activate arcuate nucleus neurons. We show that when fed a high-fat diet, both female and male GHSR-null mice eat less food, store less of their consumed calories, preferentially utilize fat as an energy substrate, and accumulate less body weight and adiposity than control mice. Similar effects on body weight and adiposity were also observed in female, but not male, GHSR-null mice fed standard chow. GHSR deletion also affected locomotor activity and levels of glycemia. These findings support the hypothesis that ghrelin-responsive pathways are an important component of coordinated body weight control. Moreover, our data suggest that ghrelin signaling is required for development of the full phenotype of diet-induced obesity.