Maximizing the potential of aggressive mouse tumor models in preclinical drug testing

Atypical teratoid rhabdoid tumor (ATRT) is an aggressive embryonal brain tumor among infants and young children. Two challenges exist for preclinical testing in ATRT. First, genetically quiet, ATRT is a difficult tumor to target molecularly. Tumor cells need to divide to propagate tumor growth—intercepting the common crossroads in cell cycle progression is a feasible strategy. KIF11 is needed for bipolar spindle formation in metaphase. We identified KIF11 as a universal target of all ATRT-molecular-subtypes. Ispinesib, a KIF11-inhibitor, effectively inhibited tumor proliferation in all seven cell lines. A second challenge—a major challenge in preclinical drug testing in-vivo among aggressive tumor models, is the narrow therapeutic window to administer drugs within the limited murine lifespan. Our most aggressive ATRT tumor model was lethal in all mice within ~ 1 month of tumor implantation. Such short-surviving mouse models are difficult to employ for preclinical drug testing due to the narrow time window to administer drugs. To overcome this time restriction, we developed a clinical staging system which allowed physically-fit mice to continue treatment, in contrast to the conventional method of fixed drug-dose-duration regimen in preclinical testing which will not be feasible in such short-surviving mouse models. We validated this approach in a second embryonal brain tumor, medulloblastoma. This is a clinically relevant, cost-efficient approach in preclinical testing for cancer and non-cancer disease phenotypes. Widely used preclinical mouse models are not the most accurate and lack the aggressive tumor spectrum found within a single tumor type. Mice bearing the most aggressive tumor spectrum progress rapidly in the limited murine life-span, resulting in a narrow therapeutic window to administer drugs, and are thus difficult to employ in preclinical testing. Our approach overcomes this challenge. We discovered ispinesib is efficacious against two embryonal brain tumor types.

Mithramycin and Analogs for Overcoming Cisplatin Resistance in Ovarian Cancer

Ovarian cancer is a highly deadly malignancy in which recurrence is considered incurable. Resistance to platinum-based chemotherapy bodes a particularly abysmal prognosis, underscoring the need for novel therapeutic agents and strategies. The use of mithramycin, an antineoplastic antibiotic, has been previously limited by its narrow therapeutic window. Recent advances in semisynthetic methods have led to mithramycin analogs with improved pharmacological profiles. Mithramycin inhibits the activity of the transcription factor Sp1, which is closely linked with ovarian tumorigenesis and platinum-resistance. This article summarizes recent clinical developments related to mithramycin and postulates a role for the use of mithramycin, or its analog, in the treatment of platinum-resistant ovarian cancer.

Delayed recanalization in acute ischemic stroke patients: Late is better than never?

Successful recanalization of the occluded vessel as early as possible has been widely accepted as the key principle of acute ischemic stroke (AIS) treatment. Unfortunately, for many years, the vast majority of AIS patients were prevented from receiving effective recanalization therapy because of a narrow therapeutic window. Recently, a series of inspiring clinical trials have indicated that more patients may benefit from delayed recanalization during an expanded therapeutic window, even up to 24 h after symptom onset. However, could potentially salvageable brain tissue (penumbra) in patients who do not receive medication within 24 h still possible to be saved?

Fisetin Prolongs Therapy Window of Brain Ischemic Stroke Using Tissue Plasminogen Activator: A Double-Blind Randomized Placebo-Controlled Clinical Trial

Recombinant tissue plasminogen activator (rt-PA) can be utilized to treat ischemic stroke with safety and effectiveness but limited by a narrow therapeutic window. In the present clinical trial among patients with stroke, we sought to evaluate the potential of fisetin to extend the therapeutic window of rt-PA treatment. Patients with stroke were divided based on their onset-to-treatment time (OTT) and then randomly assigned to receive the rt-PA treatment combined with fisetin or placebo. Primary outcome was evaluated using the National Institutes of Health Stroke scale (NIHSS), and secondary outcome was assessed by serum levels of matrix metalloproteinase (MMP) 2, MMP 9, and C-reactive protein (CRP). Fisetin dramatically improved the treatment outcomes of the patients with stroke in the delayed OTT strata, as revealed by lower NIHSS scores. The beneficial effect of fisetin was likely attributable to reduced levels of MMP-2, MMP-9, and CRP in the serum, as evidenced by strong linear correlations between serum levels of such markers with the NIHSS scores in all enrolled patients. Fisetin may possess the potential to supplement traditional rt-PA treatments among patients with stroke, particularly for those with delayed OTT, and thereby extend the otherwise narrow therapeutic window and improve the treatment outcomes.

Antiarrhythmics

Antiarrhythmic drugs are the cornerstone of supraventricular and ventricular arrhythmias therapy. Despite the increasing interest in invasive and ablative approaches to treating many arrhythmias, such as atrial fibrillation and ventricular tachycardia, antiarrhythmic drugs are still widely used for both acute management and chronic prophylaxis. Unfortunately, many antiarrhythmic drugs currently available have a narrow therapeutic window and many issues regarding potential serious adverse effects, proarrhythmic properties, and multiorgan toxicity. The current Vaughan Williams classification of antiarrhythmic drugs is shown in a table. The aim this chapter is to provide basic information regarding the most used compounds in clinical practice.

Síndrome de Neurotoxicidade Irreversível Causada por Lítio

Lithium has a narrow therapeutic window. Frequent monitoring of both serum levels and clinical signs of toxicity is warranted because toxicity may be present even when concentrations are within the therapeutic range. We report the case of a man with lithium poisoning, with persistent neurologic signs and symptoms even after removal of lithium from circulation – a diagnosis of syndrome of irreversible lithium-effectuated neurotoxicity (SILENT) was made.

Newer Oral Anticoagulants: Stroke Prevention and Pitfalls

Warfarin is very effective in preventing stroke in patients with atrial fibrillation. However, its use is limited due to fear of hemorrhagic complications, unpredictable anticoagulant effects related to multiple drug interactions and dietary restrictions, a narrow therapeutic window, frequent difficulty maintaining the anticoagulant effect within a narrow therapeutic window, and the need for inconvenient monitoring. Several newer oral anticoagulants have been approved for primary and secondary prevention of stroke in patients with non-valvular atrial fibrillation. These agents have several advantages relative to warfarin therapy. As a group, these direct oral anticoagulants (DOAC), which include the direct thrombin inhibitor, dabigatran, and the factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban), are more effective than dose adjusted warfarin for prevention of all-cause stroke (including both ischemic and hemorrhagic stroke), and have an overall more favorable safety profile. Nevertheless, an increased risk of gastrointestinal bleeding (with the exception of apixaban), increased risk for thrombotic complication with sudden discontinuation, and inability to accurately assess and reverse anticoagulant effect require consideration prior to therapy initiation, and pose a challenge for decision making in acute stroke therapy.