XBB.1.5 spike protein COVID-19 vaccine induces broadly neutralizing and cellular immune responses against EG.5.1 and emerging XBB variants.

Monovalent SARS-CoV-2 Prototype (Wuhan-Hu-1) and bivalent (Prototype + BA.4/5) COVID-19 vaccines have demonstrated a waning of vaccine-mediated immunity highlighted by lower neutralizing antibody responses against SARS-CoV-2 Omicron XBB sub-variants. The reduction of humoral immunity due to the rapid evolution of SARS-CoV-2 has signaled the need for an update to vaccine composition. A strain change for all authorized/approved vaccines to a monovalent composition with Omicron subvariant XBB.1.5 has been supported by the WHO, EMA, and FDA. Here, we demonstrate that immunization with a monovalent recombinant spike protein COVID-19 vaccine (Novavax, Inc.) based on the subvariant XBB.1.5 induces neutralizing antibodies against XBB.1.5, XBB.1.16, XBB.2.3, EG.5.1, and XBB.1.16.6 subvariants, promotes higher pseudovirus neutralizing antibody titers than bivalent (Prototype + XBB.1.5) vaccine, induces SARS-CoV-2 spike-specific Th1-biased CD4 + T-cell responses against XBB subvariants, and robustly boosts antibody responses in mice and nonhuman primates primed with a variety of monovalent and bivalent vaccines. Together, these data support updating the Novavax vaccine to a monovalent XBB.1.5 formulation for the 2023-2024 COVID-19 vaccination campaign.

A Brighton Collaboration standardized template with key considerations for a benefit/risk assessment for the Novavax COVID-19 Vaccine (NVX-CoV2373), a recombinant spike protein vaccine with Matrix-M adjuvant to prevent disease caused by SARS-CoV-2 viruses.

Novavax, a global vaccine company, began evaluating NVX-CoV2373 in human studies in May 2020 and the pivotal placebo-controlled phase 3 studies started in November 2020; five clinical studies provided adult and adolescent clinical data for over 31,000 participants who were administered NVX-CoV2373. This extensive data has demonstrated a well-tolerated response to NVX-CoV2373 and high vaccine efficacy against mild, moderate, or severe COVID-19 using a two-dose series (Dunkle et al., 2022) [1], (Heath et al., 2021) [2], (Keech et al., 2020) [3], (Mallory et al., 2022) [4]. The most common adverse events seen after administration with NVX-CoV2373 were injection site tenderness, injection site pain, fatigue, myalgia, headache, malaise, arthralgia, nausea, or vomiting. In addition, immunogenicity against variants of interest (VOI) and variants of concern (VOC) was established with high titers of ACE2 receptor-inhibiting and neutralizing antibodies in these studies (EMA, 2022) [5], (FDA, 2023) [6]. Further studies on correlates of protection determined that titers of anti-Spike IgG and neutralizing antibodies correlated with efficacy against symptomatic COVID-19 established in clinical trials (p < 0.001 for recombinant protein vaccine and p = 0.005 for mRNA vaccines for IgG levels) (Fong et al., 2022) [7]. Administration of a booster dose of the recombinant protein vaccine approximately 6 months following the primary two-dose series resulted in substantial increases in humoral antibodies against both the prototype strain and all evaluated variants, similar to or higher than the antibody levels observed in phase 3 studies that were associated with high vaccine efficacy (Dunkle et al., 2022) [1], (Mallory et al., 2022) [4]. These findings, together with the well tolerated safety profile, support use of the recombinant protein vaccine as primary series and booster regimens.

Immunogenicity and protection of a variant nanoparticle vaccine that confers broad neutralization against SARS-CoV-2 variants.

SARS-CoV-2 variants have emerged with elevated transmission and a higher risk of infection for vaccinated individuals. We demonstrate that a recombinant prefusion-stabilized spike (rS) protein vaccine based on Beta/B.1.351 (rS-Beta) produces a robust anamnestic response in baboons against SARS-CoV-2 variants when given as a booster one year after immunization with NVX-CoV2373. Additionally, rS-Beta is highly immunogenic in mice and produces neutralizing antibodies against WA1/2020, Beta/B.1.351, and Omicron/BA.1. Mice vaccinated with two doses of Novavax prototype NVX-CoV2373 (rS-WU1) or rS-Beta alone, in combination, or heterologous prime-boost, are protected from challenge. Virus titer is undetectable in lungs in all vaccinated mice, and Th1-skewed cellular responses are observed. We tested sera from a panel of variant spike protein vaccines and find broad neutralization and inhibition of spike:ACE2 binding from the rS-Beta and rS-Delta vaccines against a variety of variants including Omicron. This study demonstrates that rS-Beta vaccine alone or in combination with rS-WU1 induces antibody-and cell-mediated responses that are protective against challenge with SARS-CoV-2 variants and offers broader neutralizing capacity than a rS-WU1 prime/boost regimen alone. Together, these nonhuman primate and murine data suggest a Beta variant booster dose could elicit a broad immune response to fight new and future SARS-CoV-2 variants.

Neighbourhood walking tours for physicians-in-training.

Social and economic factors have a profound impact on patient health. However, education about these factors has been inconsistently incorporated into residency training. Neighbourhood walking tours may help physician-residents learn about the social determinants of health (SDoH). We assessed the impact of a neighbourhood walking tour on physician-residents' perceptions of SDoH, plans for counselling patients and knowledge of community resources. Using a community-based participatory research approach, in 2017 we implemented a neighbourhood walking tour curriculum for physician-residents in internal medicine, internal medicine/primary care, emergency medicine, paediatrics, combined internal medicine/paediatrics and obstetrics/gynaecology. In both pre-tour and post-tour, we asked participants to (1) rank the importance of individual-level and neighbourhood-level factors affecting patients' health, (2) describe strategies used to improve health behaviours and (3) describe knowledge of community resources. Eighty-one physician-residents participated in walks (pre-tour surveys (93% participation rate (n=75)), and post-tour surveys (53% participation rate (n=43)). Pre-tour, the factor ranked most frequently affecting patient health was 'access to primary care' (67%) compared with post-tour: 'income' (44%) and 'transportation' (44%). In describing ways to improve diet and exercise, among pre-tour survey respondents, 67% discussed individual-level strategies and 16% discussed neighbourhood-level, while among post-tour survey respondents, 39% of respondents discussed individual-level strategies and 37% discussed neighbourhood-level. Percentage of respondents aware of community resources changed from 5% to 76% (p<0.001). Walking tours helped physician-residents recognise the importance of SDoH and the value of community resources, and may have broadened frameworks for counselling patients on healthy lifestyles.

Fab and Fc contribute to maximal protection against SARS-CoV-2 following NVX-CoV2373 subunit vaccine with Matrix-M vaccination.

Recently approved vaccines have shown remarkable efficacy in limiting SARS-CoV-2-associated disease. However, with the variety of vaccines, immunization strategies, and waning antibody titers, defining the correlates of immunity across a spectrum of antibody titers is urgently required. Thus, we profiled the humoral immune response in a cohort of non-human primates immunized with a recombinant SARS-CoV-2 spike glycoprotein (NVX-CoV2373) at two doses, administered as a single- or two-dose regimen. Both antigen dose and boosting significantly altered neutralization titers and Fc-effector profiles, driving unique vaccine-induced antibody fingerprints. Combined differences in antibody effector functions and neutralization were associated with distinct levels of protection in the upper and lower respiratory tract. Moreover, NVX-CoV2373 elicited antibodies that functionally targeted emerging SARS-CoV-2 variants. Collectively, the data presented here suggest that a single dose may prevent disease via combined Fc/Fab functions but that two doses may be essential to block further transmission of SARS-CoV-2 and emerging variants.

Bayesian structural time series for biomedical sensor data: A flexible modeling framework for evaluating interventions.

The development of mobile-health technology has the potential to revolutionize personalized medicine. Biomedical sensors (e.g., wearables) can assist with determining treatment plans for individuals, provide quantitative information to healthcare providers, and give objective measurements of health, leading to the goal of precise phenotypic correlates for genotypes. Even though treatments and interventions are becoming more specific and datasets more abundant, measuring the causal impact of health interventions requires careful considerations of complex covariate structures, as well as knowledge of the temporal and spatial properties of the data. Thus, interpreting biomedical sensor data needs to make use of specialized statistical models. Here, we show how the Bayesian structural time series framework, widely used in economics, can be applied to these data. This framework corrects for covariates to provide accurate assessments of the significance of interventions. Furthermore, it allows for a time-dependent confidence interval of impact, which is useful for considering individualized assessments of intervention efficacy. We provide a customized biomedical adaptor tool, MhealthCI, around a specific implementation of the Bayesian structural time series framework that uniformly processes, prepares, and registers diverse biomedical data. We apply the software implementation of MhealthCI to a structured set of examples in biomedicine to showcase the ability of the framework to evaluate interventions with varying levels of data richness and covariate complexity and also compare the performance to other models. Specifically, we show how the framework is able to evaluate an exercise intervention's effect on stabilizing blood glucose in a diabetes dataset. We also provide a future-anticipating illustration from a behavioral dataset showcasing how the framework integrates complex spatial covariates. Overall, we show the robustness of the Bayesian structural time series framework when applied to biomedical sensor data, highlighting its increasing value for current and future datasets.

Collaboration between the Fab and Fc contribute to maximal protection against SARS-CoV-2 following NVX-CoV2373 subunit vaccine with Matrix-M™ vaccination.

Recently approved vaccines have already shown remarkable protection in limiting SARS-CoV-2 associated disease. However, immunologic mechanism(s) of protection, as well as how boosting alters immunity to wildtype and newly emerging strains, remain incompletely understood. Here we deeply profiled the humoral immune response in a cohort of non-human primates immunized with a stable recombinant full-length SARS-CoV-2 spike (S) glycoprotein (NVX-CoV2373) at two dose levels, administered as a single or two-dose regimen with a saponin-based adjuvant Matrix-M™. While antigen dose had some effect on Fc-effector profiles, both antigen dose and boosting significantly altered overall titers, neutralization and Fc-effector profiles, driving unique vaccine-induced antibody fingerprints. Combined differences in antibody effector functions and neutralization were strongly associated with distinct levels of protection in the upper and lower respiratory tract, pointing to the presence of combined, but distinct, compartment-specific neutralization and Fc-mechanisms as key determinants of protective immunity against infection. Moreover, NVX-CoV2373 elicited antibodies functionally target emerging SARS-CoV-2 variants, collectively pointing to the critical collaborative role for Fab and Fc in driving maximal protection against SARS-CoV-2. Collectively, the data presented here suggest that a single dose may prevent disease, but that two doses may be essential to block further transmission of SARS-CoV-2 and emerging variants.

Collaboration between the Fab and Fc contribute to maximal protection against SARS-CoV-2 in nonhuman primates following NVX-CoV2373 subunit vaccine with Matrix-M™ vaccination.

Recently approved vaccines have already shown remarkable protection in limiting SARS-CoV-2 associated disease. However, immunologic mechanism(s) of protection, as well as how boosting alters immunity to wildtype and newly emerging strains, remain incompletely understood. Here we deeply profiled the humoral immune response in a cohort of non-human primates immunized with a stable recombinant full-length SARS-CoV-2 spike (S) glycoprotein (NVX-CoV2373) at two dose levels, administered as a single or two-dose regimen with a saponin-based adjuvant Matrix-M™. While antigen dose had some effect on Fc-effector profiles, both antigen dose and boosting significantly altered overall titers, neutralization and Fc-effector profiles, driving unique vaccine-induced antibody fingerprints. Combined differences in antibody effector functions and neutralization were strongly associated with distinct levels of protection in the upper and lower respiratory tract, pointing to the presence of combined, but distinct, compartment-specific neutralization and Fc-mechanisms as key determinants of protective immunity against infection. Moreover, NVX-CoV2373 elicited antibodies functionally target emerging SARS-CoV-2 variants, collectively pointing to the critical collaborative role for Fab and Fc in driving maximal protection against SARS-CoV-2. Collectively, the data presented here suggest that a single dose may prevent disease, but that two doses may be essential to block further transmission of SARS-CoV-2 and emerging variants. HIGHLIGHTS: NVX-CoV2373 subunit vaccine elicits receptor blocking, virus neutralizing antibodies, and Fc-effector functional antibodies.The vaccine protects against respiratory tract infection and virus shedding in non-human primates (NHPs).Both neutralizing and Fc-effector functions contribute to protection, potentially through different mechanisms in the upper and lower respiratory tract.Both macaque and human vaccine-induced antibodies exhibit altered Fc-receptor binding to emerging mutants.

Building community resilience to prevent and mitigate community impact of gun violence: conceptual framework and intervention design.

INTRODUCTION: The USA has the highest rate of community gun violence of any developed democracy. There is an urgent need to develop feasible, scalable and community-led interventions that mitigate incident gun violence and its associated health impacts. Our community-academic research team received National Institutes of Health funding to design a community-led intervention that mitigates the health impacts of living in communities with high rates of gun violence. METHODS AND ANALYSIS: We adapted 'Building Resilience to Disasters', a conceptual framework for natural disaster preparedness, to guide actions of multiple sectors and the broader community to respond to the man-made disaster of gun violence. Using this framework, we will identify existing community assets to be building blocks of future community-led interventions. To identify existing community assets, we will conduct social network and spatial analyses of the gun violence episodes in our community and use these analyses to identify people and neighbourhood blocks that have been successful in avoiding gun violence. We will conduct qualitative interviews among a sample of individuals in the network that have avoided violence (n=45) and those living or working on blocks that have not been a location of victimisation (n=45) to identify existing assets. Lastly, we will use community-based system dynamics modelling processes to create a computer simulation of the community-level contributors and mitigators of the effects of gun violence that incorporates local population-based based data for calibration. We will engage a multistakeholder group and use themes from the qualitative interviews and the computer simulation to identify feasible community-led interventions. ETHICS AND DISSEMINATION: The Human Investigation Committee at Yale University School of Medicine (#2000022360) granted study approval. We will disseminate study findings through peer-reviewed publications and academic and community presentations. The qualitative interview guides, system dynamics model and group model building scripts will be shared broadly.

Arginine vasopressin receptor 1a is a therapeutic target for castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) recurs after androgen deprivation therapy (ADT) and is incurable. Reactivation of androgen receptor (AR) signaling in the low androgen environment of ADT drives CRPC. This AR activity occurs through a variety of mechanisms, including up-regulation of AR coactivators such as VAV3 and expression of constitutively active AR variants such as the clinically relevant AR-V7. AR-V7 lacks a ligand-binding domain and is linked to poor prognosis. We previously showed that VAV3 enhances AR-V7 activity to drive CRPC progression. Gene expression profiling after depletion of either VAV3 or AR-V7 in CRPC cells revealed arginine vasopressin receptor 1a (AVPR1A) as the most commonly down-regulated gene, indicating that this G protein-coupled receptor may be critical for CRPC. Analysis of publicly available human PC datasets showed that AVPR1A has a higher copy number and increased amounts of mRNA in advanced PC. Depletion of AVPR1A in CRPC cells resulted in decreased cell proliferation and reduced cyclin A. In contrast, androgen-dependent PC, AR-negative PC, or nontumorigenic prostate epithelial cells, which have undetectable AVPR1A mRNA, were minimally affected by AVPR1A depletion. Ectopic expression of AVPR1A in androgen-dependent PC cells conferred castration resistance in vitro and in vivo. Furthermore, treatment of CRPC cells with the AVPR1A ligand, arginine vasopressin (AVP), activated ERK and CREB, known promoters of PC progression. A clinically safe and selective AVPR1A antagonist, relcovaptan, prevented CRPC emergence and decreased CRPC orthotopic and bone metastatic growth in mouse models. Based on these preclinical findings, repurposing AVPR1A antagonists is a promising therapeutic approach for CRPC.

Patient, Family, and Community Advisory Councils in Health Care and Research: a Systematic Review.

BACKGROUND: Patient-centeredness is a characteristic of high-quality medical care and requires engaging community members in health systems' decision-making. One key patient engagement strategy is patient, family, and community advisory boards/councils (PFACs), yet the evidence to guide PFACs is lacking. Systematic reviews on patient engagement may benefit from patient input, but feasibility is unclear. METHODS: A team of physicians, researchers, and a PFAC member conducted a systematic review to examine the impact of PFACs on health systems and describe optimal strategies for PFAC conduct. We searched MEDLINE, Embase, PsycINFO, CINAHL, Scopus, and Social Science Citation Index from inception through September 2016, as well as pre-identified websites. Two reviewers independently screened and abstracted data from studies, then assessed randomized studies for risk of bias and observational studies for quality using standardized measures. We performed a realist synthesis-which asks what works, for whom, under what circumstances-of abstracted data via 12 monthly meetings between investigators and two feedback sessions with a hospital-based PFAC. RESULTS: Eighteen articles describing 16 studies met study criteria. Randomized studies demonstrated moderate to high risk of bias and observational studies demonstrated poor to fair quality. Studies engaged patients at multiple levels of the health care system and suggested that in-person deliberation with health system leadership was most effective. Studies involving patient engagement in research focused on increasing study participation. PFAC recruitment was by nomination (n = 11) or not described (n = 5). No common measure of patient, family, or community engagement was identified. Realist synthesis was enriched by feedback from PFAC members. DISCUSSION: PFACs engage communities through individual projects but evidence of their impact on outcomes is lacking. A paucity of randomized controlled trials or high-quality observational studies guide strategies for engagement through PFACs. Standardized measurement tools for engagement are needed. Strategies for PFAC recruitment should be investigated and reported. PFAC members can feasibly contribute to systematic reviews. REGISTRATION AND FUNDING SOURCE: A protocol for record eligibility was developed a priori and was registered in the PROSPERO database of systematic reviews (registration number CRD42016052817). The Department of Veterans Affairs' Office of Academic Affiliations, through the National Clinician Scholars Program, funded this study.

Targeting AR Variant-Coactivator Interactions to Exploit Prostate Cancer Vulnerabilities.

Castration-resistant prostate cancer (CRPC) progresses rapidly and is incurable. Constitutively active androgen receptor splice variants (AR-Vs) represent a well-established mechanism of therapeutic resistance and disease progression. These variants lack the AR ligand-binding domain and, as such, are not inhibited by androgen deprivation therapy (ADT), which is the standard systemic approach for advanced prostate cancer. Signaling by AR-Vs, including the clinically relevant AR-V7, is augmented by Vav3, an established AR coactivator in CRPC. Using mutational and biochemical studies, we demonstrated that the Vav3 Diffuse B-cell lymphoma homology (DH) domain interacted with the N-terminal region of AR-V7 (and full length AR). Expression of the Vav3 DH domain disrupted Vav3 interaction with and enhancement of AR-V7 activity. The Vav3 DH domain also disrupted AR-V7 interaction with other AR coactivators: Src1 and Vav2, which are overexpressed in PC. This Vav3 domain was used in proof-of-concept studies to evaluate the effects of disrupting the interaction between AR-V7 and its coactivators on CRPC cells. This disruption decreased CRPC cell proliferation and anchorage-independent growth, caused increased apoptosis, decreased migration, and resulted in the acquisition of morphological changes associated with a less aggressive phenotype. While disrupting the interaction between FL-AR and its coactivators decreased N-C terminal interaction, disrupting the interaction of AR-V7 with its coactivators decreased AR-V7 nuclear levels.Implications: This study demonstrates the potential therapeutic utility of inhibiting constitutively active AR-V signaling by disrupting coactivator binding. Such an approach is significant, as AR-Vs are emerging as important drivers of CRPC that are particularly recalcitrant to current therapies. Mol Cancer Res; 15(11); 1469-80. ©2017 AACR.

Using community-based participatory research and organizational diagnosis to characterize relationships between community leaders and academic researchers.

Sustaining collaborations between community-based organization leaders and academic researchers in community-engaged research (CEnR) in the service of decreasing health inequities necessitates understanding the collaborations from an inter-organizational perspective. We assessed the perspectives of community leaders and university-based researchers conducting community-engaged research in a medium-sized city with a history of community-university tension. Our research team, included experts in CEnR and organizational theory, used qualitative methods and purposeful, snowball sampling to recruit local participants and performed key informant interviews from July 2011-May 2012. A community-based researcher interviewed 11 community leaders, a university-based researcher interviewed 12 university-based researchers. We interviewed participants until we reached thematic saturation and performed analyses using the constant comparative method. Unifying themes characterizing community leaders and university-based researchers' relationships on the inter-organizational level include: 1) Both groups described that community-engaged university-based researchers are exceptions to typical university culture; 2) Both groups described that the interpersonal skills university-based researchers need for CEnR require a change in organizational culture and training; 3) Both groups described skepticism about the sustainability of a meaningful institutional commitment to community-engaged research 4) Both groups described the historical impact on research relationships of race, power, and privilege, but only community leaders described its persistent role and relevance in research relationships. Challenges to community-academic research partnerships include researcher interpersonal skills and different perceptions of the importance of organizational history. Solutions to improve research partnerships may include transforming university culture and community-university discussions on race, power, and privilege.

Preparing for Disaster: a Cross-Sectional Study of Social Connection and Gun Violence.

Living in communities with persistent gun violence is associated with negative social, behavioral, and health outcomes, analogous to those of a natural disaster. Taking a disaster-preparedness approach may identify targets for community-based action to respond to on-going gun violence. We assessed the relevance of adapting a disaster-preparedness approach to gun violence and, specifically, the relationship between perceived collective efficacy, its subscales of social cohesion and informal social control, and exposure to gun violence. In 2014, we conducted a cross-sectional study using a community-based participatory research approach in two neighborhoods in New Haven, CT, with high violent crime rates. Participants were ≥18 years of age and English speaking. We measured exposure to gun violence by adapting the Project on Human Development in Chicago Neighborhoods Exposure to Violence Scale. We examined the association between perceived collective efficacy, measured by the Sampson Collective Efficacy Scale, and exposure to gun violence using multivariate modeling. We obtained 153 surveys (51% response rate, 14% refusal rate, and 35% non-response rate). Ninety-five percent reported hearing gunfire, 58% had friend or family member killed by gun violence, and 33% were physically present during a shooting. In the fully adjusted model, one standard deviation higher perceived collective efficacy was associated with lower reported exposure to gun violence (ß = -0.91, p < 0.001). We demonstrated that it is possible to activate community members and local officials to engage in gun violence research. A novel, community-based approach adapted from disaster-preparedness literature may be an effective framework for mitigating exposure to gun violence in communities with persistent gun violence.

Bridging the Response to Mass Shootings and Urban Violence: Exposure to Violence in New Haven, Connecticut.

We have described self-reported exposure to gun violence in an urban community of color to inform the movement toward a public health approach to gun violence prevention. The Community Alliance for Research and Engagement at Yale School of Public Health conducted community health needs assessments to document chronic disease prevalence and risk, including exposure to gun violence. We conducted surveys with residents in six low-income neighborhoods in New Haven, Connecticut, using a neighborhood-stratified, population-based sample (n = 1189; weighted sample to represent the neighborhoods, n = 29 675). Exposure to violence is pervasive in these neighborhoods: 73% heard gunshots; many had family members or close friends hurt (29%) or killed (18%) by violent acts. Although all respondents live in low-income neighborhoods, exposure to violence differs by race/ethnicity and social class. Residents of color experienced significantly more violence than did White residents, with a particularly disparate increase among young Black men aged 18 to 34 years. While not ignoring societal costs of horrific mass shootings, we must be clear that a public health approach to gun violence prevention means focusing on the dual epidemic of mass shootings and urban violence.

Achieving Excellence Through Contemporary and Relevant Psychiatric-Mental Health Nursing Standards of Practice.

Standards of practice (SOPs) comprise competency statements, which are grounded in current knowledge and research, and provide foundations for performance that support professional accountability. The nursing profession, and specifically the psychiatric-mental health specialty of nursing practice in Canada, develops and revises practice standards regularly. The current article describes the collaborative, evidence-informed journey of the Canadian Federation of Mental Health Nurses during its fourth revision of the Canadian Psychiatric-Mental Health Nursing SOPs. An intraprofessional team of psychiatric-mental health nurses from the clinical, academic, research, and policy areas developed and nurtured collaborative processes that emphasize collegial and authentic relationships. Effective communication and a respectful learning environment supported the process for all members of the team. The current article provides recommendations for other professional organizations considering developing and/or revising SOPs.

A novel calcium-dependent mechanism of acquired resistance to IGF-1 receptor inhibition in prostate cancer cells.

Inhibition of the mitogenic insulin-like growth factor receptor 1 (IGF-1R) signaling axis is a compelling treatment strategy for prostate cancer. Combining the IGF-1R inhibitor ganitumab (formerly AMG 479) with standard of care androgen-deprivation therapy greatly delays prostate cancer recurrence in xenograft models; however, a significant proportion of these tumors ultimately acquire resistance to ganitumab. Here we describe the development of a stable and reproducible ganitumab-resistant VCaP human prostate cancer cell derivative termed VCaP/GanR to investigate the mechanism of acquired resistance to IGF-1R inhibition. Unlike parental VCaP, VCaP/GanR did not undergo apoptosis following ganitumab treatment. VCaP/GanR did not express increased levels of IGF-1R, insulin receptor, or phospho-AKT compared to parental VCaP. VCaP/GanR exhibited increased levels of phospho-S6 indicative of increased mTOR activity. However, acquired resistance to ganitumab was not dependent on increased mTOR activity in VCaP/GanR. Phospho-proteomic arrays revealed alterations in several calcium-regulated signaling components in VCaP/GanR compared to VCaP. Reduction of intracellular calcium using cell-permeable calcium-specific chelators restored ganitumab sensitivity to VCaP/GanR through inhibition of cell-cycle progression. These data suggest a new mechanism of resistance to IGF-1R inhibition involving calcium-mediated proliferation effects. Such pathways should be considered in future clinical studies of IGF-1R inhibitors in prostate cancer.