Teplinsky E.,Monter Cancer Center |
Herzog T.J.,University of Cincinnati
Expert Opinion on Pharmacotherapy | Year: 2017
Introduction: The majority of women with epithelial ovarian cancer present with advanced stage disease and there is a critical need for novel drugs and treatment strategies to improve outcomes. Trabectedin is a unique cytotoxic agent with a complex mechanism of action. It binds to guanines in the N2 position in the minor groove of DNA and its cytotoxicity involves DNA repair pathways and transcription regulation. Trabectedin’s activity is also related to the drug-induced changes of the tumor microenvironment. It has been shown to improve progression-free survival in combination with pegylated liposomal doxorubicin in patients with platinum-sensitive relapsed ovarian cancer. The most common adverse events experienced with trabectedin are nausea, vomiting, fatigue, neutropenia and transaminitis. Studies of biomarkers that are predictors of trabectedin benefit are underway. Areas covered: This review covers trabectedin’s mechanism of action and pharmacology, the clinical development of the drug in ovarian cancer, ongoing trials, and the use of biomarkers to predict efficacy to trabectedin. Expert opinion: Ongoing phase III trials with biomarker studies will help to elucidate the patient population that will best benefit from trabectedin and pave the way for personalized treatment decisions and potential future approval of trabectedin in the United States. © 2017 Informa UK Limited, trading as Taylor & Francis Group.
Anne M.,Monter Cancer Center |
Barginear M.F.,Monter Cancer Center |
Budman D.,Monter Cancer Center
OncoTargets and Therapy | Year: 2013
The histone deacetylase (HDAC) inhibitors have emerged as novel therapies for cancer. Panobinostat (LBH 589, Novartis Pharmaceuticals) is a pan-deacetylase inhibitor that is being evaluated in both intravenous and oral formulations across multiple tumor types. Comparable to the other HDACs, panobinostat leads to hyperacetylation of histones and other intracellular proteins, allowing for the expression of otherwise repressed genes, leading to inhibition of cellular proliferation and induction of apoptosis in malignant cells. Panobinostat, analogous to other HDAC inhibitors, also induces apoptosis by directly activating cellular death receptor pathways. Preclinical data suggests that panobinostat has inhibitory activity at nanomolar concentrations and appears to be the most potent clinically available HDAC inhibitor. Here we review the current status of panobinostat and discuss its role in the treatment of solid tumors. © 2013 Anne et al.
Bradley T.P.,Monter Cancer Center |
Budman D.R.,Monter Cancer Center
Annals of Hematology | Year: 2013
For more than 2,000 years, arsenic and its derivatives have shown medical utility. Owing to the toxicities and potential carcinogenicity of arsenicals, their popularity has fluctuated. The exact mechanism of action of therapeutic arsenic is not well characterized but likely to involve apoptosis, generation of reactive oxygen species, inhibition of intracellular transduction pathways, and cell functions. Arsenic trioxide has received approval for use in patients with relapsed acute promyelocytic leukemia for remission induction. Arsenic has additionally shown activity in a range of solid tumors, myelodysplastic syndrome, multiple myeloma, and in autoimmune diseases. The following is a review of the history of arsenic, its cellular metabolism, pharmacology, genetic basis of disposition, associated toxicities, and clinical efficacy. © 2013 Springer-Verlag Berlin Heidelberg.
Shapira I.,Monter Cancer Center |
Oswald M.,Feinstein Institute for Medical Research |
Khalili H.,Feinstein Institute for Medical Research |
Keogh M.,Feinstein Institute for Medical Research |
And 4 more authors.
British Journal of Cancer | Year: 2014
Background:Securing a diagnosis of ovarian cancer and establishing means to predict outcomes to therapeutics remain formidable clinical challenges. Early diagnosis is particularly important since survival rates are markedly improved if tumour is detected early.Methods:Comprehensive miRNA profiles were generated on presurgical plasma samples from 42 women with confirmed serous epithelial ovarian cancer, 36 women diagnosed with a benign neoplasm, and 23 comparably age-matched women with no known pelvic mass.Results:Twenty-two miRNAs were differentially expressed between healthy controls and the ovarian cancer group (P<0.05), while a six miRNA profile subset distinguished presurgical plasma from benign and ovarian cancer patients. There were also significant differences in miRNA profiles in presurgical plasma from women diagnosed with ovarian cancer who had short overall survival when compared to women with long overall survival (P<0.05).Conclusion:Our preliminary data support the utility of circulating plasma miRNAs to distinguish women with ovarian cancer from those with a benign mass and identify women likely to benefit from currently available treatment for serous epithelial ovarian cancer from those who may not. © 2014 Cancer Research UK.
Fields S.Z.,Monter Cancer Center |
Parshad S.,Monter Cancer Center |
Anne M.,Monter Cancer Center |
Raftopoulos H.,Monter Cancer Center |
And 5 more authors.
Expert Opinion on Investigational Drugs | Year: 2013
Introduction: Antagonists of activin receptor signaling may be beneficial for cancer-related anemia and bone disease caused by malignancies such as multiple myeloma and solid tumors. Areas covered: We review evidence of dysregulated signaling by activin receptor pathways in anemia, myeloma-associated osteolysis, and metastatic bone disease, as well as potential involvement in carcinogenesis. We then review properties of activin receptor antagonists in clinical development. Expert opinion: Sotatercept is a novel receptor fusion protein that functions as a soluble trap to sequester ligands of activin receptor type IIA (ActRIIA). Preclinically, the murine version of sotatercept increased red blood cells (RBC) in a model of chemotherapy-induced anemia, inhibited tumor growth and metastasis, and exerted anabolic effects on bone in diverse models of multiple myeloma. Clinically, sotatercept increases RBC markedly in healthy volunteers and patients with multiple myeloma. With a rapid onset of action differing from erythropoietin, sotatercept is in clinical development as a potential first-in-class therapeutic for cancer-related anemia, including those characterized by ineffective erythropoiesis as in myelodysplastic syndromes. Anabolic bone activity in early clinical studies and potential antitumor effects make sotatercept a promising therapeutic candidate for multiple myeloma and malignant bone diseases. Antitumor activity has been observed preclinically with small-molecule inhibitors of transforming growth factor-β receptor type I (ALK5) that also antagonize the closely related activin receptors ALK4 and ALK7. LY-2157299, the first such inhibitor to enter clinical studies, has shown an acceptable safety profile so far in patients with advanced cancer. Together, these data identify activin receptor antagonists as attractive therapeutic candidates for multiple diseases. © 2012 Informa UK, Ltd.
Baer M.R.,University of Maryland, Baltimore |
Baer M.R.,Roswell Park Cancer Institute |
George S.L.,Duke University |
Sanford B.L.,Duke University |
And 8 more authors.
Leukemia | Year: 2011
Untreated de novo (n=421) and secondary (n=189) acute myeloid leukemia (AML) patients ≥60 years received intensified chemotherapy, including daunorubicin 60 mg/m2 and etoposide 100 mg/m 2 during days 1, 2, 3 with cytarabine 100 mg/m 2 during days 1-7, with a second induction if needed and one consolidation course with these drugs and doses for 2, 2 and 5 days, respectively. In all, 287 (47%) achieved complete remission (CR), 136 (22%) died and 187 (31%) were non-responders. CR rates were 27, 44 and 52% for complex karyotypes, rare aberrations and neither (P<0.001), 52 and 37% for de novo and secondary AML (P=0.003), and 53 and 42% for age 60-69 and ≥70 years (P=0.015). In multivariable analysis, CR predictors included non-complex/non-rare karyotypes (P<0.001), de novo AML (P<0.001), better performance status (PS) (P<0.001) and younger age (P=0.001). Disease-free (DFS) and overall (OS) survival medians were 6.8 (95% CI: 6.2, 7.8) and 7.2 (95% CI: 6.4, 8.6) months. In multivariable analysis, DFS was shorter for complex karyotypes (P<0.001) and increasing white blood count (WBC) (P<0.001) and age (P=0.038), and OS for complex karyotypes (P<0.001), increasing WBC (P=0.001) and age (P<0.001), poorer PS (P<0.001) and secondary AML (P=0.010). Outcomes and prognostic factors were similar to those in previous Cancer and Leukemia Group B studies. © 2011 Macmillan Publishers Limited All rights reserved.
Allen S.L.,Monter Cancer Center |
Expert Opinion on Investigational Drugs | Year: 2011
Introduction: Amonafide is a novel topoisomerase II (Topo II) inhibitor and DNA intercalator that induces apoptotic signaling by blocking the binding of Topo II to DNA. Amonafide retains cytotoxic activity even in the presence of P-glycoprotein (Pgp)-mediated multi-drug resistance (MDR), a major contributor to clinical treatment failure. Areas covered: In vitro, Pgp-mediated transport (efflux) of amonafide from myeloblasts obtained from patients with secondary acute myeloid leukemia (sAML) was significantly less than efflux of daunorubicin. Amonafide has shown efficacy in patients with sAML, as well as in patients with poor prognostic characteristics such as older age and unfavorable cytogenetics, all associated with MDR. Improved antileukemic activity is observed when amonafide is given together with cytarabine, rather than as monotherapy, with a complete remission rate of ∼40% in a recent Phase II trial in sAML. The efficacy of amonafide was maintained among poor-risk subsets of patients, including older patients and patients who had previous myelodysplastic syndrome or previous leukemogenic therapy. The safety profile was acceptable and manageable. Expert opinion: Amonafide plus cytarabine may have clinical utility in patients with sAML and in other poor-risk subgroups of acute myeloid leukemia (AML). Ongoing trials will help define the role for amonafide in the treatment of poor-risk AML. © 2011 Informa UK, Ltd.
Seetharamu N.,Monter Cancer Center |
Budman D.R.,Monter Cancer Center |
Sullivan K.M.,Monter Cancer Center
Future Oncology | Year: 2016
Inhibitory ligands on tumor cells and their corresponding receptors on T cells are collectively called immune checkpoint molecules and have emerged as druggable targets that harness endogenous immunity to fight cancer. Immune checkpoint inhibitors targeting CTLA-4, PD-1 and PD-L1 have been developed for the treatment of patients with non-small-cell lung cancer and other malignancies, with impressive clinical activity, durable responses and a favorable toxicity profile. This article reviews the development, current status and future directions for some of these agents. The efficacy and safety data for drugs such as ipilimumab, nivolumab, pembrolizumab, atezolizumab and durvalumab are reviewed, along with combination strategies and response evaluation criteria. The toxicity profiles and predictive biomarkers of response are also discussed. © 2016 Future Medicine Ltd.
Shapira I.,Monter Cancer Center |
Lee A.,Feinstein Institute for Medical Research |
Vora R.,Monter Cancer Center |
Budman D.R.,Monter Cancer Center
Critical Reviews in Oncology/Hematology | Year: 2013
There is no available targeted therapy for triple-negative or its more aggressive subtype, basal-like breast cancer. Multiple therapeutic strategies based on translational knowledge have not improved the treatment options for triple negative patients. As understanding of molecular pathways that drive tumor development is rapidly increasing, it is imperative to adapt our treatment strategies to perturbations in molecular pathways driving the malignant process. Basal-like breast cancers over-express EGFR (without mutations or EGFR gene amplifications) and have p53 mutations. While EGFR drives the malignant behavior in triple negative breast cancer (TNBC), anti-EGFR therapies have fallen short of the expected results in clinical trials. Here we bring evidence that the less than optimal results of the anti-EGFR therapies may be explained in part by the increased potency of the EGFR signaling due to increased endosomal recycling. The functional connection between EGFR and endosomal trafficking in TNBC is mutant p53 found in the most aggressive forms of TNBC. Mutant p53 acquires oncogenic functions and binds p63 protein, a member of p53 family with tumor suppressor activities. In the absence of functional p63 there is an upregulation of endosomal recycling EGFR and integrin to the membrane with increased proinvasive abilities of cancer cells. Blocking endosomal trafficking combined with anti-EGFR treatments may result in better clinical outcomes in TNBC. © 2013 Elsevier Ireland Ltd.
Teplinsky E.,Monter Cancer Center |
Esteva F.J.,New York University
Current Oncology Reports | Year: 2015
Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer are at an increased risk of developing brain metastases. The incidence and prevalence of central nervous system (CNS) disease are increasing due to improved survival, which can be attributed to better systemic therapies for extracranial disease. The current standard of care for brain metastases includes a combination of surgery and/or radiation. Systemic therapies are typically reserved for patients with intracranial progression following radiation, due to their limited ability to cross the blood-brain barrier. None of the available anti-HER2 agents (trastuzumab, lapatinib, pertuzumab, and ado-trastuzumab emtansine (T-DM1)) are currently approved for the treatment of brain metastases. Research is underway evaluating novel anti-HER2 agents, which have demonstrated CNS activity. This article discusses the current data on using anti-HER2 therapies to treat CNS disease as well as the newer anti-HER2 agents, which may overcome the current challenges faced in treating brain metastases in the HER2-positive patient population. © 2015, Springer Science+Business Media New York.