Mammalian target of rapamycin as a rational therapeutic target for breast cancer treatment.

Therapies directed at endocrine receptors and human epidermal growth factor receptor 2 are important treatment options for patients with breast cancer; however, drug resistance and subsequent disease progression in patients with advanced disease is inevitable. The mammalian target of rapamycin (mTOR) is a key regulator of cell growth and proliferation implicated in the cellular processes that lead to the uncontrolled growth of cancer cells. Hence, overactivation of the mTOR pathway may also represent a key process in the development of resistance to these therapies, and interrupting this signaling cascade may alleviate resistance and help restore drug sensitivity. A number of agents that target the mTOR pathway have shown potent antitumorigenic effects in vitro, and several agents have also shown promise in treating patients with breast cancer. Everolimus and temsirolimus are the most clinically advanced agents in this class, with recent data from the BOLERO-2 study indicating significant benefit associated with everolimus when added to endocrine therapy in patients with endocrine therapy-resistant disease. In this review, we consider the translation of mTOR inhibitors from laboratory studies to large clinical trials, driven by a rational understanding of the role of mTOR in the processes that underlie breast cancer tumorigenesis.

Tocilizumab Treatment for Cytokine Release Syndrome in Hospitalized Patients With Coronavirus Disease 2019: Survival and Clinical Outcomes.

BACKGROUND: Tocilizumab, an IL-6 receptor antagonist, can be used to treat cytokine release syndrome (CRS), with observed improvements in a coronavirus disease 2019 (COVID-19) case series. RESEARCH QUESTION: The goal of this study was to determine if tocilizumab benefits patients hospitalized with COVID-19. STUDY DESIGN AND METHODS: This observational study of consecutive COVID-19 patients hospitalized between March 10, 2020, and March 31, 2020, and followed up through April 21, 2020, was conducted by chart review. Patients were treated with tocilizumab using an algorithm that targeted CRS. Survival and mechanical ventilation (MV) outcomes were reported for 14 days and stratified according to disease severity designated at admission (severe, ≥ 3 L supplemental oxygen to maintain oxygen saturation > 93%). For tocilizumab-treated patients, pre/post analyses of clinical response, biomarkers, and safety outcomes were assessed. Post hoc survival analyses were conducted for race/ethnicity. RESULTS: Among the 239 patients, median age was 64 years; 36% and 19% were black and Hispanic, respectively. Hospital census increased exponentially, yet MV census did not. Severe disease was associated with lower survival (78% vs 93%; P < .001), greater proportion requiring MV (44% vs 5%; P < .001), and longer median MV days (5.5 vs 1.0; P = .003). Tocilizumab-treated patients (n = 153 [64%]) comprised 90% of those with severe disease; 44% of patients with nonsevere disease received tocilizumab for evolving CRS. Tocilizumab-treated patients with severe disease had higher admission levels of high-sensitivity C-reactive protein (120 vs 71 mg/L; P < .001) and received tocilizumab sooner (2 vs 3 days; P < .001), but their survival was similar to that of patients with nonsevere disease (83% vs 91%; P = .11). For tocilizumab-treated patients requiring MV, survival was 75% (95% CI, 64-89). Following tocilizumab treatment, few adverse events occurred, and oxygenation and inflammatory biomarkers (eg, high-sensitivity C-reactive protein, IL-6) improved; however, D-dimer and soluble IL-2 receptor (also termed CD25) levels increased significantly. Survival in black and Hispanic patients, after controlling for age, was significantly higher than in white patients (log-rank test, P = .002). INTERPRETATION: A treatment algorithm that included tocilizumab to target CRS may influence MV and survival outcomes. In tocilizumab-treated patients, oxygenation and inflammatory biomarkers improved, with higher than expected survival. Randomized trials must confirm these findings.

Inhibition of the PI3K/AKT/mTOR Pathway in Solid Tumors.

The phosphoinositide 3-kinase (PI3K) pathway plays an integral role in many cellular processes and is frequently altered in cancer, contributing to tumor growth and survival. Small molecule inhibitors have been developed that target the three major nodes of this pathway: PI3K, AKT, and mammalian target of rapamycin. However, because oncogenic PI3K pathway activation is achieved in diverse, potentially redundant ways, the clinical efficacy of these inhibitors as monotherapies has, so far, been limited, despite demonstrating promising preclinical activity. Moreover, pathway activation is associated with resistance to other therapies; thus, in combination, PI3K pathway inhibitors could restore therapeutic sensitivity to these agents. To maximize therapeutic benefit, drug combinations and schedules must be explored to identify those with the highest efficacy and lowest toxicity overlap. In addition, defining appropriate patient subpopulations, for both monotherapy and drug combinations, will be important. However, identifying predictive biomarkers remains a challenge.

Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a phase I trial.

PURPOSE: To investigate safety, tolerability, dose-related pharmacologic properties, and pharmacodynamics of ZD1839 (gefinitib, Iressa; AstraZeneca Pharmacueticals, Wilmington, DE), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in patients with solid tumor types known to express or highly express EGFR. METHODS: This was an open-label, phase I, dose escalation safety/tolerability trial of oral ZD1839 (150 to 1,000 mg/d), administered once daily for 28-continuous-day cycles until disease progression or undue toxicity. RESULTS: Of 71 (69 assessable for safety; 58 for efficacy) patients at seven dose levels, most had non-small-cell lung (n = 39) or head and neck (n = 18) cancer, and 68 of 71 patients received prior cancer therapy (two or more regimens in 54 patients [78%]). Diarrhea and rash, the primary dose-limiting toxicities (DLTs), occurred at 800 mg. Frequent treatment-related grade 1/2 adverse events were diarrhea (55%), asthenia (44%), and acne-like follicular rash (46%). At doses >or= 800 mg, 45% of patients required dose reductions. No increased or cumulative toxicity was observed over 250 patient-months of exposure. Pharmacokinetic analysis showed that steady-state occurred by day 7, interpatient exposure was more variable than intrapatient exposure, and variability of exposure did not change with dose. One patient experienced a partial response, but antitumor activity manifested mainly as prolonged stable disease (45% of patients >or= 3 months, 22% >or= 6 months, and 7.2% >or= 1 year). No relationship between dose, response, or duration on study was observed. CONCLUSION: Rash and diarrhea, generally mild and tolerable at doses

Vascular targeting agents.

The role of the vascular network of a tumor has been the focus of much recent research. Angiogenesis, or the growth of new tumor blood vessels, was initially the main target in the development of novel antitumor agents. More recently, new therapeutic strategies have been designed to destroy established tumor blood vessels. These vascular targeting agents (VTAs) exert their action by producing a rapid shutdown of tumor blood flow, resulting in ischemia and tumor cell necrosis. VTAs can be broadly divided into biologic agents and small molecules. In contrast to the biologic agents, drug-based vascular targeting molecules have developed much further, with many clinical trials ongoing. Evidence suggests that VTAs may be useful as single agents but can be more effective when used in combination with other therapeutic regimens.