SMARCB1 Gene Therapy Using a Novel Tumor-Targeted Nanomedicine Enhances Anti-Cancer Efficacy in a Mouse Model of Atypical Teratoid Rhabdoid Tumors.

Purpose: Atypical teratoid rhabdoid tumor (ATRT) is a deadly, fast-growing form of pediatric brain cancer with poor prognosis. Most ATRTs are associated with inactivation of SMARCB1, a subunit of the chromatin remodeling complex, which is involved in developmental processes. The recent identification of SMARCB1 as a tumor suppressor gene suggests that restoration of SMARCB1 could be an effective therapeutic approach. Methods: We tested SMARCB1 gene therapy in SMARCB1-deficient rhabdoid tumor cells using a novel tumor-targeted nanomedicine (termed scL-SMARCB1) to deliver wild-type SMARCB1. Our nanomedicine is a systemically administered immuno-lipid nanoparticle that can actively cross the blood-brain barrier via transferrin receptor-mediated transcytosis and selectively target tumor cells via transferrin receptor-mediated endocytosis. We studied the antitumor activity of the scL-SMARCB1 nanocomplex either as a single agent or in combination with traditional treatment modalities in preclinical models of SMARCB1-deficient ATRT. Results: Restoration of SMARCB1 expression by the scL-SMARCB1 nanocomplex blocked proliferation, and induced senescence and apoptosis in ATRT cells. Systemic administration of the scL-SMARCB1 nanocomplex demonstrated antitumor efficacy as monotherapy in mice bearing ATRT xenografts, where the expression of exogenous SMARCB1 modulates MYC-target genes. scL-SMARCB1 demonstrated even greater antitumor efficacy when combined with either cisplatin-based chemotherapy or radiation therapy, resulting in significantly improved survival of ATRT-bearing mice. Conclusion: Collectively, our data suggest that restoring SMARCB1 function via the scL-SMARCB1 nanocomplex may lead to therapeutic benefits in ATRT patients when combined with traditional chemoradiation therapies.

A Pralidoxime Nanocomplex Formulation Targeting Transferrin Receptors for Reactivation of Brain Acetylcholinesterase After Exposure of Mice to an Anticholinesterase Organophosphate.

Introduction: Organophosphates are among the deadliest of known chemicals based on their ability to inactivate acetylcholinesterase in neuromuscular junctions and synapses of the central and peripheral nervous systems. The consequent accumulation of acetylcholine can produce severe acute toxicities and death. Oxime antidotes act by reactivating acetylcholinesterase with the only such reactivator approved for use in the United States being 2-pyridine aldoxime methyl chloride (a.k.a., pralidoxime or 2-PAM). However, this compound does not cross the blood-brain barrier readily and so is limited in its ability to reactivate acetylcholinesterase in the brain. Methods: We have developed a novel formulation of 2-PAM by encapsulating it within a nanocomplex designed to cross the blood-brain barrier via transferrin receptor-mediated transcytosis. This nanocomplex (termed scL-2PAM) has been subjected to head-to-head comparisons with unencapsulated 2-PAM in mice exposed to paraoxon, an organophosphate with anticholinesterase activity. Results and Discussion: In mice exposed to a sublethal dose of paraoxon, scL-2PAM reduced the extent and duration of cholinergic symptoms more effectively than did unencapsulated 2-PAM. The scL-2PAM formulation was also more effective than unencapsulated 2-PAM in rescuing mice from death after exposure to otherwise-lethal levels of paraoxon. Improved survival rates in paraoxon-exposed mice were accompanied by a higher degree of reactivation of brain acetylcholinesterase. Conclusion: Our data indicate that scL-2PAM is superior to the currently used form of 2-PAM in terms of both mitigating paraoxon toxicity in mice and reactivating acetylcholinesterase in their brains.

A Second Career for p53 as A Broad-Spectrum Antiviral?

As the world exits the global pandemic caused by the previously unknown SARS-CoV-2, we also mark the 30th anniversary of p53 being named "molecule of the year" by Science based on its role as a tumor suppressor. Although p53 was originally discovered in association with a viral protein, studies on its role in preventing carcinogenesis have far overshadowed research related to p53's role in viral infections. Nonetheless, there is an extensive body of scientific literature demonstrating that p53 is a critical component of host immune responses to viral infections. It is striking that diverse viruses have independently developed an impressive repertoire of varied mechanisms to counter the host defenses that are mediated by and through p53. The variety of ways developed by viruses to disrupt p53 in their hosts attests to the protein's importance in combatting viral pathogens. The present perspective aims to make the case that p53 ought to be considered a virus suppressor in addition to a tumor suppressor. It is hoped that additional research aimed at more fully understanding the role of p53 in antiviral immunity will result in the world being better positioned for the next pandemic than it was when SARS-CoV-2 emerged to produce COVID-19.

A Novel P53 Nanomedicine Reduces Immunosuppression and Augments Anti-PD-1 Therapy for Non-Small Cell Lung Cancer in Syngeneic Mouse Models.

Lung cancer is among the most common and lethal cancers and warrants novel therapeutic approaches to improving patient outcomes. Although immune checkpoint inhibitors (ICIs) have demonstrated substantial clinical benefits, most patients remain unresponsive to currently approved ICIs or develop resistance after initial response. Many ongoing clinical studies are investigating combination therapies to address the limited efficacy of ICIs. Here, we have assessed whether p53 gene therapy via a tumor-targeting nanomedicine (termed SGT-53) can augment anti-programmed cell death-1 (PD-1) immunotherapy to expand its use in non-responding patients. Using syngeneic mouse models of lung cancers that are resistant to anti-PD-1, we demonstrate that restoration of normal p53 function potentiates anti-PD-1 to inhibit tumor growth and prolong survival of tumor-bearing animals. Our data indicate that SGT-53 can restore effective immune responses against lung cancer cells by reducing immuno-suppressive cells (M2 macrophages and regulatory T cells) and by downregulating immunosuppressive molecules (e.g., galectin-1, a negative regulator of T cell activation and survival) while increasing activity of cytotoxic T cells. These results suggest that combining SGT-53 with anti-PD-1 immunotherapy could increase the fraction of lung cancer patients that responds to anti-PD-1 therapy and support evaluation of this combination particularly in patients with ICI-resistant lung cancers.

Nanomedicine-Based Gene Delivery for a Truncated Tumor Suppressor RB94 Promotes Lung Cancer Immunity.

Because lung cancer remains the most common and lethal of cancers, novel therapeutic approaches are urgently needed. RB94 is a truncated form of retinoblastoma tumor suppressor protein with elevated anti-tumor efficacy. Our investigational nanomedicine (termed scL-RB94) is a tumor-targeted liposomal formulation of a plasmid containing the gene encoding RB94. In this research, we studied anti-tumor and immune modulation activities of scL-RB94 nanocomplex in preclinical models of human non-small cell lung cancer (NSCLC). Systemic treatment with scL-RB94 of mice bearing human NSCLC tumors significantly inhibited tumor growth by lowering proliferation and increasing apoptosis of tumor cells in vivo. scL-RB94 treatment also boosted anti-tumor immune responses by upregulating immune recognition molecules and recruiting innate immune cells such as natural killer (NK) cells. Antibody-mediated depletion of NK cells blunted the anti-tumor activity of scL-RB94, suggesting that NK cells were crucial for the observed anti-tumor activity in these xenograft models. Treatment with scL-RB94 also altered the polarization of tumor-associated macrophages by reducing immune-suppressive M2 macrophages to lower immune suppression in the tumor microenvironment. Collectively, our data suggest that the efficacy of scL-RB94 against NSCLC is due to an induction of tumor cell death as well as enhancement of innate anti-tumor immunity.

TP53 Gene Therapy as a Potential Treatment for Patients with COVID-19.

SGT-53 is a novel investigational agent that comprises an immunoliposome carrying a plasmid vector driving expression of the human TP53 gene that encodes wild-type human p53. SGT-53 is currently in phase II human trials for advanced pancreatic cancer. Although p53 is best known as a tumor suppressor, its participation in both innate and adaptive immune responses is well documented. It is now clear that p53 is an important component of the host response to various viral infections. To facilitate their viral life cycles, viruses have developed a diverse repertoire of strategies for counteracting the antiviral activities of host immune system by manipulating p53-dependent pathways in host cells. Coronaviruses reduce endogenous p53 levels in the cells they infect by enhancing the degradation of p53 in proteasomes. Thus, interference with p53 function is an important component in viral pathogenesis. Transfection of cells by SGT-53 has been shown to transiently produce exogenous p53 that is active as a pleiotropic transcription factor. We herein summarize the rationale for repurposing SGT-53 as a therapy for infection by SARS-CoV-2, the pathogen responsible for the COVID-19 pandemic. Because p53 regulation was found to play a crucial role in different infection stages of a wide variety of viruses, it is rational to believe that restoring p53 function based on SGT-53 treatment may lead to beneficial therapeutic outcomes for infectious disease at large including heretofore unknown viral pathogens that may emerge in the future.

A tumor-targeting nanomedicine carrying the p53 gene crosses the blood-brain barrier and enhances anti-PD-1 immunotherapy in mouse models of glioblastoma.

Despite its anticipated clinical potential, anti-PD-1 immunotherapy has only yielded poor outcomes in recent clinical trials for glioblastoma patients. Strategies combining anti-PD-1 antibody with other treatment modalities are being explored to alter the immunosuppressive microenvironment that appears to characterize these anti-PD-1-insensitive tumors. Here, we evaluated whether introducing wild-type p53 gene via a tumor-targeting nanomedicine (termed SGT-53) could provide immune stimulation and augment anti-PD-1 therapy in mouse syngeneic GL261 tumor models (either subcutaneous or intracranial). In both models, anti-PD-1 monotherapy had no demonstrable therapeutic effect. However, combining anti-PD-1 with our investigational nanomedicine SGT-53 was very effective in inhibiting tumor growth, inducing tumor cell apoptosis and increasing intratumoral T-cell infiltration. A significant survival benefit was observed in mice bearing intracranial glioblastoma receiving combination treatment. Importantly, SGT-53 upregulated PD-L1 expression both in vitro and in vivo. Transcriptome analysis revealed modulation of genes linked to either cancer progression or immune activation after combination treatment. Our data suggest that SGT-53 can boost antitumor immunity and sensitize glioblastoma to anti-PD-1 therapy by converting immunologically "cold" tumors into "hot" tumors. Combining SGT-53 with anti-PD-1 might benefit more patients from anti-PD-1 immunotherapy and our data support evaluation of this combination in patients with glioblastoma.

Advancing Cancer Research in Africa Through Early-Career Awards: The BIG Cat Initiative.

PURPOSE: The burden of cancer in Africa is growing rapidly, and increased cancer research on the continent is a critical component of an effective response. In 2010, the US National Cancer Institute, in partnership with the African Organization for Research and Training in Cancer, launched the Beginning Investigator Grant for Catalytic Research (BIG Cat) initiative to support cancer research projects conducted by early-career African investigators. METHODS: To date, BIG Cat has provided 18 awards of up to $50,000 to support 2-year cancer research projects. In 2017, the National Cancer Institute evaluated BIG Cat's early outcomes for cancer research and impacts on career development and local cancer research capacity. Data collection consisted of a review of project documentation and a survey fielded to the 12 investigators who had completed their BIG Cat awards. RESULTS: BIG Cat-supported research projects have generated locally relevant findings that address a range of cancer sites and multiple areas of scientific interest. The 11 survey respondents produced 43 scholarly products (e.g., publications, presentations) about findings from their BIG Cat research. They reported increases in cancer research funding applications and awards after receipt of the BIG Cat award compared with before the award. They also reported increased resources for cancer research, participation in teaching and mentoring on cancer research, and supervision of cancer research staff. Investigators identified scientific mentoring as a key facilitator of the success of their BIG Cat projects and limited time and funding as key challenges. CONCLUSION: Findings provide early evidence that BIG Cat advanced locally relevant cancer research and facilitated career advancement and development of local cancer research capacity. Findings have implications for the design of future related efforts.

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor.

The tumor suppressor p53 responds to genotoxic and oncogenic stresses by inducing cell cycle arrest and apoptosis. Recent studies suggest that p53 also participates in the regulation of cellular immune responses. Here, we have investigated the potential of p53 gene therapy to augment immune checkpoint inhibition by combining an anti-programmed cell death protein 1 (PD1) antibody with SGT-53, our investigational nanomedicine carrying a plasmid encoding human wild-type p53. In three syngeneic mouse tumor models examined including a breast cancer, a non-small cell lung carcinoma, and a glioblastoma, SGT-53 sensitized otherwise refractory tumors to anti-PD1 antibody. The involvement of p53 in enhancing anti-PD1 immunotherapy appears to be multifaceted, since SGT-53 treatment increased tumor immunogenicity, enhanced both innate and adaptive immune responses, and reduced tumor-induced immunosuppression in a 4T1 breast tumor model. In addition, SGT-53 alleviates a fatal xenogeneic hypersensitivity associated with the anti-PD1 antibody in this model. Our data suggest that restoring p53 function by SGT-53 is able to boost anti-tumor immunity to augment anti-PD1 therapy by sensitizing tumors otherwise insensitive to anti-PD1 immunotherapy while reducing immune-related adverse events.

Nanocomplex-based TP53 gene therapy promotes anti-tumor immunity through TP53- and STING-dependent mechanisms.

Loss or mutation of TP53 has been linked to alterations in anti-tumor immunity as well as dysregulation of cell cycle and apoptosis. We explored immunologic effects and mechanisms following restoration of wild-type human TP53 cDNA in murine oral cancer cells using the therapeutic nanocomplex scL-53. We demonstrated scL-53 induces dose-dependent expression of TP53 and induction of apoptosis and immunogenic cell death. We further demonstrated both TP53-dependent and independent induction of tumor cell immunogenicity through the use of blocking mAbs, nanocomplex loaded with DNA plasmid with or without TP53 cDNA, empty nanocomplex and siRNA knockdown techniques. TP53-independent immune modulation was observed following treatment with nanocomplex loaded with DNA plasmid lacking TP53 cDNA and abrogated in STING-deficient tumor cells, supporting the presence of a cytoplasmic DNA sensing, STING-dependent type-I IFN response. Cooperatively, TP53- and STING-dependent alterations sensitized tumor cells to CTL-mediated lysis, which was further enhanced following reversal of adaptive immune resistance with PD-1 mAb. In vivo, combination scL-53 and PD-1 mAb resulted in growth control or rejection of established tumors that was abrogated in mice depleted of CD8+ cells or in STING deficient mice. Cumulatively, this work demonstrates 1) a direct anti-tumor effects of functional TP53; 2) non-redundant TP53- and STING-dependent induction of tumor cell immunogenicity following scL-53 treatment; and 3) that adaptive immune resistance following scL-53 treatment can be reversed with PD-based immune checkpoint blockade, resulting in the rejection or control of syngeneic murine tumors. These data strongly support the clinical combination of scL-53 and immune checkpoint blockade.

Targeted nanocomplex carrying siRNA against MALAT1 sensitizes glioblastoma to temozolomide.

Intrinsic therapeutic resistance especially in cancer stem cells (CSCs) together with extensive tumor cell infiltration and restricted permeation of the blood-brain barrier (BBB) by drugs may all contribute to the treatment failure in patients with glioblastoma multiforme (GBM). Accumulating evidence suggests that long non-coding RNA (lncRNA), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays a role in tumor cell infiltration and therapeutic resistance of GBM. Using our tumor-targeted nanocomplex, we have modulated the expression of MALAT1 and investigated its impact on GBM cells. Importantly, our nanocomplex is able to target CSCs that are considered to be the prime culprits in therapeutic resistance and recurrence of GBM. Attenuation of MALAT1 by RNA interference significantly lowered the growth, motility and stemness of GBM cells. In addition, silencing of MALAT1 clearly improved the sensitivity of GBM cells to chemotherapeutic agents including the current first-line therapy of GBM [temozolomide (TMZ)]. In animal models of GBM, tumor involution with a modest but statistically significant survival benefit was achieved with concurrent treatment of TMZ and nanocomplex-mediated silencing of MALAT1. These results suggest that combining standard TMZ treatment with lncRNA-targeting therapies using our nanocomplex could substantially enhance the very poor prognosis for GBM patients.

Nanotherapeutics for Gene Modulation that Prevents Apoptosis in the Brain and Fatal Neuroinflammation.

The failure of therapeutic agents to cross the blood-brain barrier (BBB) has been a major impediment in the treatment of neurological disorders and brain tumors. We have addressed this issue using an immunoliposome nanocomplex (designated scL) that delivers therapeutic nucleic acids across the BBB into the deep brain via transcytosis mediated by transferrin receptors. We validated brain delivery of payloads after systemic administration by monitoring uptake of fluorescently labeled payloads and by confirming up- or down-modulation of specific target gene expression in the brain, mainly in neuronal cells. As proof of concept for the therapeutic potential of our delivery system, we employed scL delivering an siRNA targeting tumor necrosis factor alpha to suppress neuroinflammation and neuronal apoptosis and to protect mice in lethal endotoxemia triggered by bacterial lipopolysaccharide. Brain delivery of therapeutic payloads via scL has major implications for the development of treatments for neurological disorders and brain tumors.

Nanomedicine: Past, present and future - A global perspective.

Nanomedicine is an emerging and rapidly evolving field and includes the use of nanoparticles for diagnosis and therapy of a variety of diseases, as well as in regenerative medicine. In this mini-review, leaders in the field from around the globe provide a personal perspective on the development of nanomedicine. The focus lies on the translation from research to development and the innovation supply chain, as well as the current status of nanomedicine in industry. The role of academic professional societies and the importance of government funding are discussed. Nanomedicine to combat infectious diseases of poverty is highlighted along with other pertinent examples of recent breakthroughs in nanomedicine. Taken together, this review provides a unique and global perspective on the emerging field of nanomedicine.

Breast cancer by age at diagnosis in the Gharbiah, Egypt, population-based registry compared to the United States Surveillance, Epidemiology, and End Results Program, 2004-2008.

OBJECTIVE: Although breast cancers (BCs) in young women often display more aggressive features, younger women are generally not screened for early detection. It is important to understand the characteristics of young onset breast cancer to increase awareness in this population. This analysis includes all ages, with emphasis placed on younger onset BC in Egypt as compared to the United States. METHODS: BC cases in the Gharbiah cancer registry (GCR), Egypt, were compared to those in the Surveillance, Epidemiology, and End Results (SEER) database. This analysis included 3,819 cases from the GCR and 273,019 from SEER diagnosed 2004-2008. RESULTS: GCR cases were diagnosed at later stages, with <5% diagnosed at Stage I and 12% diagnosed at Stage IV. 48% of all SEER cases were diagnosed at Stage I, dropping to 30% among those ≤40. Significant differences in age, tumor grade, hormone receptor status, histology, and stage exist between GCR and SEER BCs. After adjustment, GCR cases were nearly 45 times more likely to be diagnosed at stage III and 16 times more likely to be diagnosed at stage IV than SEER cases. CONCLUSIONS: Future research should examine ways to increase literacy about early detection and prompt therapy in young cases.

Barriers to overcome for effective cancer control in Africa.

Cancer control in Africa is complicated due to large differences in cancer incidence between countries caused by differences in exposure to known risk factors. For example, substantial differences are seen when selected cancers in north Africa are compared with those in sub-Saharan Africa. In the future, population growth and demographic shifts are likely to have profound effects on the prevalence of cancer across the continent. Likewise, many factors outside of health care such as language differences, conflict, and poverty can affect cancer control efforts. Although cooperation in cancer control efforts is desirable, differences in cultural and geopolitical factors that characterise African countries and their populations, together with the sheer size of the continent, present unique challenges to effective cancer control. This Series paper discusses factors related to the size, diversity, and conditions within Africa that present barriers to optimal collaboration in cancer control efforts across the continent.

Effective treatment of glioblastoma requires crossing the blood-brain barrier and targeting tumors including cancer stem cells: The promise of nanomedicine.

Glioblastoma multiforme (GBM) is the most aggressive and lethal type of brain tumor. Both therapeutic resistance and restricted permeation of drugs across the blood-brain barrier (BBB) play a major role in the poor prognosis of GBM patients. Accumulated evidence suggests that in many human cancers, including GBM, therapeutic resistance can be attributed to a small fraction of cancer cells known as cancer stem cells (CSCs). CSCs have been shown to have stem cell-like properties that enable them to evade traditional cytotoxic therapies, and so new CSC-directed anti-cancer therapies are needed. Nanoparticles have been designed to selectively deliver payloads to relevant target cells in the body, and there is considerable interest in the use of nanoparticles for CSC-directed anti-cancer therapies. Recent advances in the field of nanomedicine offer new possibilities for overcoming CSC-mediated therapeutic resistance and thus significantly improving management of GBM. In this review, we will examine the current nanomedicine approaches for targeting CSCs and their therapeutic implications. The inhibitory effect of various nanoparticle-based drug delivery system towards CSCs in GBM tumors is the primary focus of this review.

A comparison of criteria to identify inflammatory breast cancer cases from medical records and the Surveillance, Epidemiology and End Results data base, 2007-2009.

Inflammatory breast cancer (IBC) is a relatively rare and extremely aggressive form of breast cancer that is diagnosed clinically. Standardization of clinical diagnoses is challenging, both nationally and internationally; moreover, IBC coding definitions used by registries have changed over time. This study aimed to compare diagnostic factors of IBC reported in a U.S. Surveillance, Epidemiology, and End Results (SEER) registry to clinical criteria found in the medical records of all invasive breast cancer cases at a single institution. We conducted a medical record review of all female invasive breast cancers (n = 915) seen at an NCI-designated comprehensive cancer center in Detroit from 2007 to 2009. IBC cases were identified based on the presence of the main clinical characteristics of the disease (erythema, edema, peau d'orange). We compared the proportion of IBC out of all breast cancers, using these clinical criteria and the standard SEER IBC codes. In the reviewed cases, the clinical criteria identified significantly more IBC cases (n = 74, 8.1%) than the standard IBC SEER definition (n = 19, 2.1%; p < 0.0001). No IBC cases were identified in the cancer center records using the SEER pathologic coding, which requires the diagnosis of inflammatory carcinoma on the pathology report, a notation that is rarely made. Emphasis must be placed on the documentation of clinical and pathologic characteristics of IBC in the medical record, so that analysis of putative IBC subtypes will be possible. Our results indicate the need for a consensus on the definition of IBC to be utilized in future research.

Trends in Breast Cancer Incidence Rates by Age and Stage at Diagnosis in Gharbiah, Egypt, over 10 Years (1999-2008).

Background. This study was undertaken to evaluate trends in breast cancer incidence in Egypt from 1999 to 2008 and to make projections for breast cancer occurrence for the years 2009-2015. Patients and Methods. We utilized joinpoint regression and average annual percent change (AAPC) measures with 95% confidence intervals (CI) to describe the trends in breast cancer incidence rates from the Gharbiah Cancer Registry by age and stage at diagnosis and to estimate expected breast cancer caseloads for 2009-2015. Results. From 1999 to 2008, the AAPC in breast cancer incidence rates in Gharbiah significantly increased among women 50 years and older and among localized tumors (AAPC %, 95% CI, 3.1% to 8.0%). Our results predict a significant increase in breast cancer caseloads from 2009 to 2015 among women aged 30-39 (AAPC %, 95% CI, 0.9% to 1.1%) and among women aged 40-49 years (AAPC %, 95% CI, 1.0% to 2.6%). Conclusion. These results have important implications for allocating limited resources, managing treatment needs, and exploring the consequences of prior interventions and/or changing risk factors in Egypt and other developing countries at the same stages of demographic and health transitions.