Considerations for treatment duration in responders to immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) have improved overall survival for cancer patients, however, optimal duration of ICI therapy has yet to be defined. Given ICIs were first used to treat patients with metastatic melanoma, a condition that at the time was incurable, little attention was initially paid to how much therapy would be needed for a durable response. As the early immunotherapy trials have matured past 10 years, a significant per cent of patients have demonstrated durable responses; it is now time to determine whether patients have been overtreated, and if durable remissions can still be achieved with less therapy, limiting the physical and financial toxicity associated with years of treatment. Well-designed trials are needed to identify optimal duration of therapy, and to define biomarkers to predict who would benefit from shorter courses of immunotherapy. Here, we outline key questions related to health, financial and societal toxicities of over treating with ICI and present four unique clinical trials aimed at exposing criteria for early cessation of ICI. Taken together, there is a serious liability to overtreating patients with ICI and future work is warranted to determine when it is safe to stop ICI.

PARP Inhibition in Cancer: An Update on Clinical Development.

PARP (poly(ADP-ribose) polymerase) inhibitors represent a novel class of anti-cancer therapy; they take advantage of synthetic lethality and induce cell death by exploiting a defect in DNA repair. This class of medication was initially evaluated in patients with BRCA-associated tumors, but efficacy was also demonstrated in other populations. Since 2014, four PARP inhibitors have been approved in various indications: olaparib, niraparib, and rucaparib in high-grade serous ovarian cancer, and olaparib and talazoparib in metastatic breast cancer. The exact indications and study populations vary slightly between the different approvals in both disease states but there is significant overlap. PARP inhibitors continue to be investigated in ongoing clinical trials. In line with other targeted therapies, benefit appears to be strongest in a distinct population of patients with BRCA mutations or other defects in homologous recombination repair. Combination therapies, which include anti-angiogenesis agents and immunotherapy, show promise as a strategy to broaden efficacy for unselected patients. Initial studies of PARP inhibitors in combination with chemotherapy were limited by toxicity, but further studies are underway. To date, head-to-head trials comparing various PARP inhibitors have not been conducted, so questions remain in terms of choosing a PARP inhibitor to administer when indications overlap, as well as how to sequence these medications. Here we review both completed and ongoing clinical trials involving PARP inhibitors and mechanisms of resistance to this class of drugs.

Aldoxorubicin for the treatment of soft tissue sarcoma.

Intoduction: Soft tissue sarcomas (STS) encompass a group of rare tumors arising from mesenchymal tissue. Traditionally, anthracycline-based chemotherapy, with doxorubicin, is the main treatment for advanced STS. Areas covered: Aldoxorubicin is a doxorubicin derivative containing a carboxylic hydrazone and serves as a prodrug of doxorubicin. It covalently binds to albumin in the blood until reaching the acidic tumor environment, which dissolves the hydrazone linker, thus releasing doxorubicin into the tissue. In this review paper, we analyze the pharmacokinetics, current phase I, phase II, and phase III trials, as well as adverse effect profile of aldoxorubicin in patients with advanced STS. Expert opinion: Aldoxorubicin represents a promising drug for treatment of sarcomas. The drug has minimal cardiac toxicity, which represents a significant advantage to doxorubicin. Preliminary phase 3 study results demonstrate PFS advantage in patients with leiomyosarcoma and liposarcoma. However, more studies are needed to establish the role of aldoxorubicin in sarcoma treatment.

Statins and pancreatic cancer.

Pancreatic cancer remains among the most lethal cancers, despite ongoing advances in treatment for all stages of the disease. Disease prevention represents another opportunity to improve patient outcome, with metabolic syndrome and its components, such as diabetes, obesity and dyslipidemia, having been recognized as modifiable risk factors for pancreatic cancer. In addition, statins have been shown to potentially reduce pancreatic cancer risk and to improve survival in patients with a combination of metabolic syndrome and pancreatic cancer. Furthermore, preclinical studies have demonstrated that statins exhibit antitumor effects in pancreatic cancer cell lines in vitro and animal models in vivo, in addition to delaying the progression of pancreatic intraepithelial neoplasia to pancreatic ductal adenocarcinoma (PDAC) and inhibiting PDAC formation in conditional K-Ras mutant mice. The mechanisms by which statins produce anticancer effects remain poorly understood, although appear to involve inhibition of the mevalonate/cholesterol synthesis pathway, thus blocking the synthesis of intermediates important for prenylation and activation of the Ras/mitogen-activated protein kinase 1 signaling pathway. Furthermore, statins have been identified to modulate the phosphoinositide 3-kinase/Akt serine/threonine kinase 1 and inflammation signaling pathways, and to alter the expression of genes involved in lipid metabolism, which are important for PDAC growth and proliferation. In addition, statins have been demonstrated to exhibit further antitumor mechanisms in a number of other cancer types, which are beyond the scope of the present review. In the present review, current evidence highlighting the potential of statins as chemopreventive agents in pancreatic cancer is presented, and the antitumor mechanisms of statins elucidated thus far in this disease are discussed.

Clinical development of reovirus for cancer therapy: An oncolytic virus with immune-mediated antitumor activity.

Reovirus is a double-stranded RNA virus with demonstrated oncolysis or preferential replication in cancer cells. The oncolytic properties of reovirus appear to be dependent, in part, on activated Ras signaling. In addition, Ras-transformation promotes reovirus oncolysis by affecting several steps of the viral life cycle. Reovirus-mediated immune responses can present barriers to tumor targeting, serve protective functions against reovirus systemic toxicity, and contribute to therapeutic efficacy through antitumor immune-mediated effects via innate and adaptive responses. Preclinical studies have demonstrated the broad anticancer activity of wild-type, unmodified type 3 Dearing strain reovirus (Reolysin(®)) across a spectrum of malignancies. The development of reovirus as an anticancer agent and available clinical data reported from 22 clinical trials will be reviewed.

A Rare Finding of a BRAF Mutation in Renal Cell Carcinoma with Response to BRAF-Directed Targeted Therapy.

Whole exome sequencing can identify somatic mutations in malignant tumors and allow for personalized and novel treatment of common malignancies. Mutations in the BRAF gene are rare in renal cell carcinoma, and thus, BRAF inhibitors are not considered standard in the treatment of these cancers. Here, we report a case of a patient with a rare BRAF-mutated metastatic renal cell carcinoma who obtained a good clinical response to BRAF inhibition. This case underscores the value of precision medicine in an era of rapidly evolving therapeutics for malignancies.

Adnectin-targeted inhibitors: rationale and results.

Adnectins are a family of binding proteins derived from the 10th type III domain of human fibronectin (10Fn3), which is part of the immunoglobulin superfamily and normally binds integrin. The 10Fn3 has the potential for broad therapeutic applications given its structural stability, ability to be manipulated, and its abundance in the human body. The most commonly studied adnectin is CT-322, which is an inhibitor of vascular endothelial growth factor receptor-2. A bispecific adnectin, El-Tandem, has also been developed and binds to epidermal growth factor receptor and insulin-like growth factor-1 receptor simultaneously. Pre-clinical studies have shown promising results in relation to reducing tumor growth, decreasing microvessel density, and promoting normalization of tumor architecture. The phase I trial with CT-322 demonstrates relatively low toxicities. However, the phase II study done with CT-322 in recurrent glioblastoma does not reveal as promising results.

Left ventricular hypertrophy in valvular aortic stenosis: mechanisms and clinical implications.

Valvular aortic stenosis is the second most prevalent adult valve disease in the United States and causes progressive pressure overload, invariably leading to life-threatening complications. Surgical aortic valve replacement and, more recently, transcatheter aortic valve replacement effectively relieve the hemodynamic burden and improve the symptoms and survival of affected individuals. However, according to current American College of Cardiology/American Heart Association guidelines on the management of valvular heart disease, the indications for aortic valve replacement, including transcatheter aortic valve replacement, are based primarily on the development of clinical symptoms, because their presence indicates a dismal prognosis. Left ventricular hypertrophy develops in a sizeable proportion of patients before the onset of symptoms, and a growing body of literature demonstrates that regression of left ventricular hypertrophy resulting from aortic stenosis is incomplete after aortic valve replacement and associated with adverse early postoperative outcomes and worse long-term outcomes. Thus, reliance on the development of symptoms alone without consideration of structural abnormalities of the myocardium for optimal timing of aortic valve replacement potentially constitutes a missed opportunity to prevent postoperative morbidity and mortality from severe aortic stenosis, especially in the face of the quickly expanding indications of lower-risk transcatheter aortic valve replacement. The purpose of this review is to discuss the mechanisms and clinical implications of left ventricular hypertrophy in severe valvular aortic stenosis, which may eventually move to center stage as an indication for aortic valve replacement in the asymptomatic patient.

Takotsubo Cardiomyopathy.

Takotsubo cardiomyopathy (TTC) is an acute, stress-induced cardiomyopathy with an increased prevalence in post-menopausal women. The syndrome is most frequently precipitated by an acute emotional or physical stressor and mimics acute myocardial infarction with symptoms, electrocardiogram (ECG) changes and cardiac troponin elevation that are indistinguishable from those caused by plaque rupture or coronary thrombosis. Diagnosis of TTC is made when coronary angiography reveals no obstructive coronary artery disease and the left ventricle demonstrates apical ballooning and basal hypercontractility. Other ventricular patterns have also been described. An abnormal myocardial response to the catecholamine surge from an emotional or a physical stressor is implicated in the pathophysiology, but the reasons for the high prevalence of TTC presentations in post-menopausal women are unknown. Several mechanisms including multi-vessel coronary vasospasm, endothelial and coronary microvascular dysfunction and direct catecholamine toxicity have been proposed. No specific guidelines for treatment of TTC have been established, but treatment is based on the American Heart Association/American College of Cardiology guidelines for acute coronary syndrome/acute myocardial infarction and heart failure guidelines. In this review article, we discuss the characteristic clinical presentation of TTC and the commonly proposed mechanisms.