New York State 1115 Demonstration Independent Evaluation: Interim Report.

The broad goals of New York State's Medicaid Section 1115 Waiver are to enroll a majority of Medicaid beneficiaries into managed care, increase access and service quality, and expand coverage to more low-income New Yorkers. The RAND Corporation was competitively selected as the independent evaluator to assess two components under this 1115 Demonstration Waiver: the Managed Long-Term Care (MLTC) program and the 12-month continuous eligibility policy, which guarantees enrollees Medicaid coverage regardless of changes in income in the 12 months after eligibility determination and enrollment. This final interim evaluation examines whether these two components have helped achieve the program's goals. The RAND team's analyses show that the Demonstration has expanded access to managed care through mandatory MLTC enrollment and 12-month continuous eligibility. The team found no evidence of a significant change in patient safety or quality of care. The authors note that, although this means that there is no evidence the Demonstration achieved the goal of improving quality of care, increasing access without compromising quality of care is a success in its own right.

Profiles of Two Glycaemia Modifying Drugs on the Expression of Rat and Human Sulfotransferases.

AIMS: To study the effects of blood glucose regulating compounds on human and rat sulfotransferases (SULTs) expressions. BACKGROUND: Phase-II enzymes, sulfotransferases catalyze the sulfuryl-group-transfer to endogenous/exogenous compounds. The alteration of expressions of SULTs may have influence on the sulfation of its substrate and other biomolecules. OBJECTIVES: The influence of the altered biotransformation might alter different biochemical events, drug-drug interactions and bioaccumulation or excretion pattern of certain drug. METHODS: In this brief study, diabetes-inducing drug streptozotocin (STZ; 10 or 50 mg/kg to male Sprague Dawley rat for 2 weeks) or hyperglycemia controlling drug tolbutamide (TLB 0.1 or 10µM to human hepato-carcinoma cells, HepG2 for 10 days) was applied and the SULTs expressions were verified. Extensive protein-protein (STa, SULT2A1/DHEAST) interactions were studied by the STRING (Search-Tool-for-the-Retrieval-of-Interacting Genes/Proteins) Bioinformatics-software. RESULTS: Present result suggests that while STZ increased the STa (in rat) (dehydroepiandrosterone catalyzing SULT; DHEAST in human HepG2), tolbutamide decreased PPST (phenol catalyzing SULT) and DHEAST activity in human HepG2 cells. Moderate decreases of MPST (monoamine catalyzing SULT) and EST (estrogen catalyzing) activities are noticed in this case. STa/DHEAST was found to be highly interactive to SHBG/- sex-hormone-binding-globulin; PPARα/lipid-metabolism-regulator; FABP1/fatty-acid-binding-protein. CONCLUSION: Streptozotocin and tolbutamide, these two glycaemia-modifying drugs demonstrated regulation of rat and human SULTs activities. The reciprocal nature of these two drugs on SULTs expression may be associated with their contrasting abilities in influencing glucose-homeostasis. Possible association of certain SULT-isoform with hepatic fat-regulations may indicate an unfocused link between calorie-metabolism and the glycemic-state of an individual. Explorations of this work may uncover the role of sulfation metabolism of specific biomolecule on cellular glycemic regulation.

Oxidative Stress-induced Toxicity and DNA Stability in Some Agri-field Based Livestock/Insect by Widely used Pesticides.

AIM AND OBJECTIVE: Humans continuously use pesticides in the field to control the pest population and weeds for considerable agricultural productivity. Side-by species like grazinganimals, insects and other species are adversely affected by or become resistant to pesticides. Insects, birds and cattle are highly abundant dwellers of the agriculture-field and represent three distinct phyla having versatile physiological features. Besides higher agricultural-productivity, protection to several species will maintain ecological/environmental balance. Studies on the effect of widely used pesticides on their DNA-stability and important enzymatic-activities are insufficient. MATERIALS AND METHODS: Antioxidant-activity (Superoxide-dismutase; SOD/Catalase- by gelzymogram- assay) and DNA-stability (fragmentation-assay) in hepatic/gut tissues were studied after in vitro exposure of Chlorpyrifos, Fenvalerate, Nimbecidine or Azadirachtin to goat/cow/poultry-hen/insect. RESULTS: In general, all pesticides were found to impair enzymatic-activities. However, lower organisms were affected more than higher vertebrates by azadirachtin-treatment. DNA fragmentation was found more in insects/poultry-birds than that of the cattle in hepatic/gut tissues. Inversely, toxicity/antioxidant marker-enzymes were more responsive in insect gut-tissues. However, mitochondrialtoxicity revealed variable effects on different species. It has been noticed that chlorpyrifos is the most toxic pesticide, followed by Fenvalerate/Nimbecidine (Azadirachtin, AZT). Nevertheless, AZT revealed its higher DNA-destabilizing effects on the field-insects as compared to the other animals. CONCLUSION: Field-insects are highly integrated into the ecosystem and the local bio-geo-chemical cycle, which may be impaired. Pesticides may have toxic effects on higher vertebrates and may sustain in the soil after being metabolized into their different derivatives. Some of the sensitive biochemical parameters of this organism may be used as a biomarker for pesticide toxicity.

Protection against Mitochondrial Oxidative-Stress by Flesh-Extract of Edible Freshwater Snail Bellamya bengalensis Prevents Arsenic Induced DNA and Tissue Damage.

AIMS: Arsenic has carcinogenic properties because of the formation of Reactive Oxygen Species (ROS). ROS damages different macromolecules, tissues and organs, and severely exhausts cellular antioxidants. BACKGROUND: Cytosolic and mitochondrial contribution of ROS production by arsenic are not well reported. In regard to the issues of therapy against arsenic or any other toxicity, natural product has gained its popularity due to its less side-effects and non-invasive nature. OBJECTIVES: Here, as an ethnomedicine, the flesh-extract (BBE; 100mg/100g bw) of Bellamya bengalensis (an aquatic mollusk) was applied in arsenic intoxicated (0.6 ppm/100g bw/for 28 days alone or in combination with BBE) experimental rats. Our objective was to study the anti-oxidative and anti-apoptotic role of BBE in hepato-gastrointestinal tissue damage by arsenic. METHODS: DNA fragmentation assay, catalase activity (gel-zymogram assay) suggests that BBE has a strong protective role against arsenic toxicity, which is decisively demonstrated in hepatic histoarchitecture study by HE (hematoxylin and eosin) staining and by intestinal PAS (Periodic Acid Schiff) staining. RESULTS: Measurement of mitochondrial-membrane-potential by fluorescent microcopy clearly demonstrated less membrane damage and lower release of the redox-active inner-membrane product (cytochrome-C, ubiquinone, etc.) in BBE supplemented group compared to that of the only arsenic fed group. The present study clearly suggests that mitochondrial disintegrity is one of the major causes of ROS mediated tissue damage by arsenic. CONCLUSION: This study also offers an option for prevention/treatment against arsenic toxicity and its carcinogenicity by widely available low-cost, non-invasive Bellamya extract by protecting cytoskeleton, DNA and mitochondria in the cell.

A multidisciplinary review of the policy, intellectual property rights, and international trade environment for access and affordability to essential cancer medications.

In 2015, the World Health Organization (WHO) Expert Committee approved the addition of 16 cancer medicines to the WHO Model List of Essential Medicines (EML), bringing the total number of cancer medicines on the list to 46. This change represented the first major revision to the EML oncology section in recent history and reinforces international recognition of the need to ensure access and affordability for cancer treatments. Importantly, many low and middle-income countries rely on the EML, as well as the children's EML, as a guide to establish national formularies, and moreover use these lists as tools to negotiate medicine pricing. However, EML inclusion is only one component that impacts cancer treatment access. More specifically, factors such as intellectual property rights and international trade agreements can interact with EML inclusion, drug pricing, and accessibility. To better understand this dynamic, we conducted an interdisciplinary review of the patent status of EML cancer medicines compared to other EML noncommunicable disease medicines using the 17th, 18th, 19th, 20th, and 21st editions of the list. We also explored the interaction of intellectual property rights with the international trade regime and how trade agreements can and do impact cancer treatment access and affordability. Based on this analysis, we conclude that patent status is simply one factor in the complex international environment of health systems, IPR policies, and trade regimes and that aligning these oftentimes disparate interests will require shared global governance across the cancer care continuum.

Impact of Project ECHO Models of Medical Tele-Education: a Systematic Review.

BACKGROUND: Extension for Community Healthcare Outcomes (ECHO) and related models of medical tele-education are rapidly expanding; however, their effectiveness remains unclear. This systematic review examines the effectiveness of ECHO and ECHO-like medical tele-education models of healthcare delivery in terms of improved provider- and patient-related outcomes. METHODS: We searched English-language studies in PubMed, Embase, and PsycINFO databases from 1 January 2007 to 1 December 2018 as well as bibliography review. Two reviewers independently screened citations for peer-reviewed publications reporting provider- and/or patient-related outcomes of technology-enabled collaborative learning models that satisfied six criteria of the ECHO framework. Reviewers then independently abstracted data, assessed study quality, and rated strength of evidence (SOE) based on Cochrane GRADE criteria. RESULTS: Data from 52 peer-reviewed articles were included. Forty-three reported provider-related outcomes; 15 reported patient-related outcomes. Studies on provider-related outcomes suggested favorable results across three domains: satisfaction, increased knowledge, and increased clinical confidence. However, SOE was low, relying primarily on self-reports and surveys with low response rates. One randomized trial has been conducted. For patient-related outcomes, 11 of 15 studies incorporated a comparison group; none involved randomization. Four studies reported care outcomes, while 11 reported changes in care processes. Evidence suggested effectiveness at improving outcomes for patients with hepatitis C, chronic pain, dementia, and type 2 diabetes. Evidence is generally low-quality, retrospective, non-experimental, and subject to social desirability bias and low survey response rates. DISCUSSION: The number of studies examining ECHO and ECHO-like models of medical tele-education has been modest compared with the scope and scale of implementation throughout the USA and internationally. Given the potential of ECHO to broaden access to healthcare in rural, remote, and underserved communities, more studies are needed to evaluate effectiveness. This need for evidence follows similar patterns to other service delivery models in the literature.

Targeting small cell lung cancer harboring PIK3CA mutation with a selective oral PI3K inhibitor PF-4989216.

PURPOSE: Constitutive activation of phosphoinositide 3-kinase (PI3K) occurs frequently in many human tumors via either gene mutation in the p110α catalytic subunit of PI3K or functional loss of tumor suppressor PTEN. Patients with small-cell lung cancer (SCLC) have very poor prognosis and survival rates such that an effective targeted therapy is in strong demand for these patients. In this study, we characterized the highly selective oral PI3K inhibitor, PF-4989216, in preclinical SCLC models to investigate whether targeting the PI3K pathway is an effective targeted therapy option for SCLCs that harbor a PIK3CA mutation. EXPERIMENTAL DESIGN: A panel of SCLC cell lines with PIK3CA mutation or PTEN loss were treated with PF-4989216 in several in vitro assays, including PI3K pathway signaling, cell viability, apoptosis, cell-cycle progression, and cell transformation. SCLC cell lines that were sensitive in vitro to PF-4989216 were further evaluated by in vivo animal studies to determine the pharmacokinetic/pharmacodynamic relationship and tumor growth inhibition (TGI) by PF-4989216 treatment. RESULTS: PF-4989216 inhibited PI3K downstream signaling and subsequently led to apoptosis induction, and inhibition in cell viability, transformation, and xenograft tumor growth in SCLCs harboring PIK3CA mutation. In SCLCs with PTEN loss, PF-4989216 also inhibited PI3K signaling but did not induce BCL2-interacting mediator (BIM)-mediated apoptosis nor was there any effect on cell viability or transformation. These results implicate differential tumorigenesis and apoptosis mechanisms in SCLCs harboring PIK3CA mutation versus PTEN loss. CONCLUSIONS: Our results suggest that PF-4989216 is a potential cancer drug candidate for patients with SCLC with PIK3CA mutation but not PTEN loss.

The clinical assessment of ischaemia modified albumin and troponin I in the early diagnosis of the acute coronary syndrome.

BACKGROUND: An early identification of the patients with the Acute Coronary Syndrome (ACS) is of prime importance, due to the associated very high mortality. Only about 22% of the patients who present at the emergency cardiology care centres with chest pain, have coronary disease. Ischaemia modified albumin has already been licensed by the US Food and Drug Administration for the diagnosis of suspected myocardial ischaemia. AIM: The goal of the present study was to assess the diagnostic value of serum ischaemia modified albumin and to compare it with sensitive cardiac troponin I in patients with the acute coronary syndromes like unstable angina and acute myocardial infarction. METHODS: A diagnostic case control study was conducted on 102 patients who presented to the Emergency Department within 6 hrs of having acute chest pain and on 110 healthy age and sex matched volunteers who formed the control group. The serum Ischaemia Modified Albumin level was estimated by the albumin cobalt binding test by using a digital spectrophotometer, while Troponin I was measured by doing an immunofluroscence assay. A receiver operating characteristic curve was established for ischaemia modified albumin, to determine the cut-off point. The sensitivity and the specificity of ischaemia modified albumin and troponin I for the detection of acute coronary syndromes, were analyzed. The results of ischaemia modified albumin and troponin I alone and in combination, were correlated. RESULTS: The ischaemia modified albumin (p<0.05) and the troponin I (p<0.001) concentrations were significantly higher in acute myocardial infarction and in unstable angina than in the healthy controls. The sensitivity and the specificity of ischaemia modified albumin for the detection of acute coronary syndromes was 88% and 93% as compared to 87% and 75% respectively for troponin I. The combined use of ischaemia modified albumin and troponin I significantly enhanced the sensitivity to 96%. The area which was under the Receiver Operating Characteristic (ROC) curve of ischaemia modified albumin in acute coronary syndromes was 0.90. CONCLUSION: Ischaemia modified albumin is a useful biochemical marker for the early diagnosis of acute coronary syndrome. The combined use of ischaemia modified albumin and cardiac troponin I enhances the sensitivity and specificity. Hence, a combination of ischaemia modified albumin and cardiac troponin I can be used as a more precise diagnostic marker for Acute Coronary Syndrome.

miR-221 promotes tumorigenesis in human triple negative breast cancer cells.

Patients with triple-negative breast cancers (TNBCs) typically have a poor prognosis. TNBCs are characterized by their resistance to apoptosis, aggressive cellular proliferation, migration and invasion, and currently lack molecular markers and effective targeted therapy. Recently, miR-221/miR-222 have been shown to regulate ERα expression and ERα-mediated signaling in luminal breast cancer cells, and also to promote EMT in TNBCs. In this study, we characterized the role of miR-221 in a panel of TNBCs as compared to other breast cancer types. miR-221 knockdown not only blocked cell cycle progression, induced cell apoptosis, and inhibited cell proliferation in-vitro but it also inhibited in-vivo tumor growth by targeting p27(kip1). Furthermore, miR-221 knockdown inhibited cell migration and invasion by altering E-cadherin expression, and its regulatory transcription factors Snail and Slug in human TNBC cell lines. Therefore, miR-221 functions as an oncogene and is essential in regulating tumorigenesis in TNBCs both in vitro as well as in vivo.

Highly selective 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase.

We report the SAR around a series of 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase. 2-Aminophenethyl analogs demonstrate excellent potency but moderate kinase selectivity, while 2-aminobenzyl analogs that fill the Ala571 subpocket exhibit good inhibition activity and excellent kinase selectivity.

Optimization of highly selective 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase.

Optimization of the ADME properties of a series of 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase resulted in the identification of highly selective compounds with properties suitable for use as in vitro and in vivo tools to probe the effects of Sky inhibition.

Targeting the mTOR pathway in tumor malignancy.

The mammalian target of rapamycin (mTOR) plays a critical role in the regulation of cell growth, proliferation,and metabolism by integrating growth factor stimulation and energy/nutrient input through a complex signaling network.The mTOR kinase is a part of two structurally and functionally distinct multiple protein complexes, mTORC1 and mTORC2. The mammalian target of rapamycin complex 1 (mTORC1) is rapamycin-sensitive and mediates temporal control of cell growth by regulating several cellular processes, such as translation, transcription, and nutrient transport while the mammalian target of rapamycin complex 2 (mTORC2) is in sensitive to rapamycin and is involved in spatial control of cell growth via cytoskeleton regulation. Here we discuss the mechanism of mTOR regulation in tumor malignancy through a variety of signaling pathways and the potential of mTOR inhibitors for the treatment of cancer.

Attenuation of serum ferritin and iron burden by intake of antioxidants in beta thalassemia major.

It has been anticipated that iron and ferritin burden in patients with beta thalassemia major is associated with enhanced free radical formation and blemished antioxidant defense system. The goal of study was to scrutinize impact of serum iron, total iron binding capacity (TIBC), ferritin and erythrocyte catalase in patients with beta thalassemia major. 140 beta thalassemia major patients were studied before and after supplementation of antioxidants for one month, and status was compared with 140 age and sex matched healthy controls. A significant elevation was found in the levels of serum iron and ferritin (P < 0.001) with concomitant decrease in erythrocyte catalase (P < 0.001) in patients when compared with controls. After one month supplementation of antioxidants, catalase was elevated significantly (P < 0.001) and marginal rise in serum TIBC concentration increased marginally while iron and ferritin were decreased marginally (P > 0.05) when compared with controls and baselines values. Beta thalassemia major children receive multiple blood transfusions, and are at risk of secondary iron overload induced oxidative stress. These effects may be help to minimize with supplementation of antioxidants.

Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04979064 through Structure-Based Drug Design.

PI3K, AKT, and mTOR are key kinases from PI3K signaling pathway being extensively pursued to treat a variety of cancers in oncology. To search for a structurally differentiated back-up candidate to PF-04691502, which is currently in phase I/II clinical trials for treating solid tumors, a lead optimization effort was carried out with a tricyclic imidazo[1,5]naphthyridine series. Integration of structure-based drug design and physical properties-based optimization yielded a potent and selective PI3K/mTOR dual kinase inhibitor PF-04979064. This manuscript discusses the lead optimization for the tricyclic series, which both improved the in vitro potency and addressed a number of ADMET issues including high metabolic clearance mediated by both P450 and aldehyde oxidase (AO), poor permeability, and poor solubility. An empirical scaling tool was developed to predict human clearance from in vitro human liver S9 assay data for tricyclic derivatives that were AO substrates.

Targeting 3-phosphoinoside-dependent kinase-1 to inhibit insulin-like growth factor-I induced AKT and p70 S6 kinase activation in breast cancer cells.

Binding of IGF to IGF-IR activates PI3K to generate PIP3 which in turn recruits and activates proteins that contain a pleckstrin homology (PH) domain, including AKT and PDK1. PDK1 is highly expressed in breast tumor samples and breast cancer cell lines. Here we demonstrate that targeting PDK1 with the potent and selective PDK1 inhibitor PF-5177624 in the IGF-PI3K pathway blocks breast cancer cell proliferation and transformation. Breast cancer cell lines MCF7 and T47D, representing the luminal ER positive subtype and harboring PIK3CA mutations, were most responsive to IGF-I induction resulting in upregulated AKT and p70S6K phosphorylation via PDK1 activation. PF-5177624 downregulated AKT and p70S6K phosphorylation, blocked cell cycle progression, and decreased cell proliferation and transformation to block IGFR-I induced activation in breast cancer cells. These results may provide insight into clinical strategies for developing an IGFR-I inhibitor and/or a PDK1 inhibitor in luminal breast cancer patients.

Targeting of 4-1BB by monoclonal antibody PF-05082566 enhances T-cell function and promotes anti-tumor activity.

4-1BB (CD137, TNFRSF9) is a costimulatory receptor expressed on several subsets of activated immune cells. Numerous studies of mouse and human T cells indicate that 4-1BB promotes cellular proliferation, survival, and cytokine production. 4-1BB agonist mAbs have demonstrated efficacy in prophylactic and therapeutic settings in both monotherapy and combination therapy tumor models and have established durable anti-tumor protective T-cell memory responses. PF-05082566 is a fully human IgG2 that binds to the extracellular domain of human 4-1BB with high affinity and specificity. In preclinical studies, this agonist antibody demonstrated its ability to activate NF-κB and induce downstream cytokine production, promote leukocyte proliferation, and inhibit tumor growth in a human PBMC xenograft tumor model. The mechanism of action and robust anti-tumor efficacy of PF-05082566 support its clinical development for the treatment of a broad spectrum of human malignancies.

Discovery of novel, potent, and selective inhibitors of 3-phosphoinositide-dependent kinase (PDK1).

Analogues substituted with various amines at the 6-position of the pyrazine ring on (4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrazin-2-ylmethanone were discovered as potent and selective inhibitors of PDK1 with potential as anticancer agents. An early lead with 2-pyridine-3-ylethylamine as the pyrazine substituent showed moderate potency and selectivity. Structure-based drug design led to improved potency and selectivity against PI3Kα through a combination of cyclizing the ethylene spacer into a saturated, five-membered ring and substituting on the 4-position of the aryl ring with a fluorine. ADME properties were improved by lowering the lipophilicity with heteroatom replacements in the saturated, five-membered ring. The optimized analogues have a PDK1 Ki of 1 nM and >100-fold selectivity against PI3K/AKT-pathway kinases. The cellular potency of these analogues was assessed by the inhibition of AKT phosphorylation (T308) and by their antiproliferation activity against a number of tumor cell lines.

Effective targeting of triple-negative breast cancer cells by PF-4942847, a novel oral inhibitor of Hsp 90.

PURPOSE: Triple-negative breast cancer (TNBC) patients have poor prognoses and survival outcomes such that the development of new targeted therapies is in strong demand. Mechanisms associated with high proliferation and aggressive tumor progression, such as PI3K/PTEN aberration, epidermal growth factor receptor (EGFR) overexpression, and cell-cycle upregulation, play important roles in TNBC. The molecular chaperone Hsp90 is required for the conformational maturation and stability of a variety of proteins in multiple pathways, such as EGFR, AKT, Raf, cdk4, etc. Therefore, an Hsp90 inhibitor may show therapeutic benefit in TNBC by targeting multiple pathways. EXPERIMENTAL DESIGN: The novel oral Hsp90 inhibitor PF-4942847 was characterized in multiple in vitro and in vivo assays to determine its antitumor activity in TNBC cell lines. In addition, the correlation of AKT degradation and Hsp70 induction in host peripheral blood lymphocytes (PBL) and xenograft tumors was determined. RESULTS: PF-4942847 induces degradation of multiple client proteins, cell-cycle block, apoptosis, and inhibits cell proliferation in TNBC lines, subsequently leading to tumor growth inhibition in mouse xenograft models. The correlation of AKT degradation and Hsp70 induction between PBLs and xenograft tumors reveals a differential modulation of Hsp90 activity between host and tumor tissues, and suggests that AKT degradation in PBLs may serve as a pharmacodynamic biomarker in future clinical development. CONCLUSIONS: The novel oral Hsp90 inhibitor, PF-4942847, is a candidate for clinical development in TNBC by collaboratively targeting multiple signaling pathways. In addition, AKT degradation in PBLs may serve as a biomarker in clinical development.

Dual functional monoclonal antibody PF-04605412 targets integrin alpha5beta1 and elicits potent antibody-dependent cellular cytotoxicity.

Integrin α5ß1 is overexpressed in tumor-associated stroma and cancer cells, and has been implicated in angiogenesis, tumor survival, and metastasis. Antibody-dependent cellular cytotoxicity (ADCC) by immune effector cells has been shown to contribute to clinical efficacy for several IgG1 monoclonal antibody (mAb) therapeutics. Taking advantage of these two mechanisms, we generated a fully human, fragment crystalizable (Fc)-engineered IgG1 mAb, PF-04605412 (PF-5412), which specifically neutralizes α5 and binds the Fcγ receptors (FcγR) with enhanced affinity. In vitro, PF-5412 potently inhibited α5ß1-mediated intracellular signaling, cell adhesion, migration, and endothelial cell (EC) tubulogenesis. PF-5412 induced significantly greater ADCC in α5-expressing tumor cells and ECs compared with a wild-type IgG1 (IgG1/wt) or IgG2 of identical antigen specificity. The degree of ADCC correlated with the abundance of natural killer (NK) cells in the peripheral blood mononuclear cells but was independent of donor FcγRIIIa polymorphism. In animal studies, PF-5412 displayed robust and dose-dependent antitumor efficacy superior to that observed with IgG1/wt, IgG2, or IgG4 of identical antigen specificity. The degree of efficacy correlated with α5 expression, macrophage and NK cell infiltration, and NK activity in the tumor. Depletion of host macrophages abrogated antitumor activity, suggesting a critical contribution of macrophage-mediated antitumor activity of PF-5412. Combination of PF-5412 with sunitinib significantly improved antitumor efficacy compared with either agent alone. The dual mechanism of action and robust antitumor efficacy of PF-5412 support its clinical development for the treatment of a broad spectrum of human malignancies.