Control Of Cancer Growth Research Articles

At2-MMP is required for attenuation of cell proliferation during wound healing in incised Arabidopsis inflorescence stems.

Wound healing of partially incised Arabidopsis inflorescence stems constitutes cell proliferation that initiates mainly in pith tissues about three days after incision, and that the healing process completes in about seven days. Although the initiation mechanisms of cell proliferation have been well documented, the suppression mechanisms remain elusive. Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases well-known as proteolytic enzymes in animal systems functioning in extracellular matrix remodeling during physiological and pathological processes, including tissue differentiation, growth, defense, wound healing, and control of cancer growth. In this study, we report At2-MMP might contribute to the suppression mechanism of cell proliferation during tissue-repair process of incised inflorescence stems. At2-MMP transcript was gradually upregulated from day 0 to 5 after incision, and slightly decreased on day 7. Morphological analysis of incised stem of defected mutant at2-mmp revealed significantly enhanced cell proliferation around the incision site. Consistent with this, semi-quantitative analysis of dividing cells displayed a significant increment in the number of dividing cells in at2-mmp as compared to WT. These results showed that the upregulation of At2-MMP at the later stage of wound-healing process is likely to be involved in the completion of the process by attenuating the cell proliferation.

Setting the Stage for Cancer: Stay Soft and Optimistic.

In the Netherlands, one out of two people will be confronted with the diagnosis of cancer sometime in their life. Against this increased number of patients, a large proportion luckily can be cured. Today, a rather high proportion of people receive treatment to control cancer growth or stabilize the disease, sometimes, for the rest of their lives. If such long-standing treatment is administered for more than 10-20 years, the stage of cancer is presently often not referred to as "palliative" anymore, but much more often as "chronic." It could be argued that regardless of the cancer disease stage you are in and whether you are or can be cured, your cancer diagnosis nevertheless has become part of your life, including the experience of chronicity. Discussions surrounding the chronicity of cancer in the context of cancer are still ongoing. This is especially the case because "experiencing chronicity" is dependent on the type of cancer and is less applicable in cancers where the prognosis is often less than one year, such as is more frequently the case with lung or pancreatic cancer. In all situations, experiencing chronicity nevertheless brings along uncertainty, either with or without chronic stress. Combatting stress by choosing the right wording, maintaining an optimistic stance along with physical activity and/or psychosocial education seems important to optimize well-being and to stabilize tumor growth or remove the tumor. In conclusion, chronicity in the context of treating and caring for cancer seems a somewhat gray area. However, regardless in how we, as medical professionals, speak about cancer with long-standing disease trajectories (that sometimes even can be cured), it first of all seems important to approach, take care, and treat patients well. This can facilitate discussions with patients about their disease and disease experiences. Moreover, it can stimulate patients themselves to take responsibility for their own health, which can be of added value to the entire disease trajectory.

Comparison of drug treatment intent in stage IV solid tumors in EU4+UK.

e23323 Background: The goal of cancer treatment may vary based on multiple factors. This study uses real-world data to compare treatment intent, and its evolution over time among patients with solid tumors; whilst we focus on stage IV cohorts, a comparison vs. stage I-III patients is also made, for context. Methods: Ipsos’ Global Oncology Monitor is a multi-stakeholder, physician-reported syndicated patient record database. 3,308 solid tumor-treating physicians (France = 834, Germany = 709, Italy = 578, Spain = 626, UK = 561) were screened for seniority and caseload and submitted data on 329,154 patients (France = 64,985, Germany = 77,709, Italy = 64,507, Spain = 65,427, UK = 56,526). Data were collected online from January 2020 to September 2023. Sample data were projected to the wider clinical population using market sizing extrapolations. Results: Of all solid tumor patients reported, regardless of stage, control cancer spread and/or growth (extend life) is the most common cited goal by sampled physicians when choosing drug therapy for the patient in question (average ~50% reported patients). This is followed by intent of eliminating cancer cells to undetectable levels (curative), while the intent to ease cancer symptoms (palliative) is typically less likely to be selected. Treatment intent at stage I-III showed similar trends, with curative being the most common goal (average ~70% of reported patients). When focusing on Stage IV solid tumors we observe life extension generally emerging as the main intention; a more nuanced analysis reveals similarity between Germany and Spain, where palliative intent is cited more often by sampled physicians compare to other regional counterparts. These differences are shown in Table 1. Little change seen in curative intent from 2020 to 2023 across all regions, except UK, where a downward trend is reflected from Q3 2022 onwards with a concurrent increase in extend life. Conclusions: This study indicates that treating to cure is a common aim for EU4+UK sampled physicians when giving drug therapy to stage I-III solid tumor patients, whilst extending life is the notable goal when considering stage IV patients. Additional analysis of tumor- and region-specific changes over time may help establish any potential influences on drug treatment choice due to factors such as reimbursement and treatment type availability. Further investigation using comparator cohort is warranted. [Table: see text]

Analysis of the nischarin expression across human tumor types reveals its context-dependent role and a potential as a target for drug repurposing in oncology.

Nischarin was reported to be a tumor suppressor that plays a critical role in breast cancer initiation and progression, and a positive prognostic marker in breast, ovarian and lung cancers. Our group has found that nischarin had positive prognostic value in female melanoma patients, but negative in males. This opened up a question whether nischarin has tumor type-specific and sex-dependent roles in cancer progression. In this study, we systematically examined in the public databases the prognostic value of nischarin in solid tumors, regulation of its expression and associated signaling pathways. We also tested the effects of a nischarin agonist rilmenidine on cancer cell viability in vitro. Nischarin expression was decreased in tumors compared to the respective healthy tissues, most commonly due to the deletions of the nischarin gene and promoter methylation. Unlike in healthy tissues where it was located in the cytoplasm and at the membrane, in tumor tissues nischarin could also be observed in the nuclei, implying that nuclear translocation may also account for its cancer-specific role. Surprisingly, in several cancer types high nischarin expression was a negative prognostic marker. Gene set enrichment analysis showed that in tumors in which high nischarin expression was a negative prognostic marker, signaling pathways that regulate stemness were enriched. In concordance with the findings that nischarin expression was negatively associated with pathways that control cancer growth and progression, nischarin agonist rilmenidine decreased the viability of cancer cells in vitro. Taken together, our study lays a ground for functional studies of nischarin in a context-dependent manner and, given that nischarin has several clinically approved agonists, provides rationale for their repurposing, at least in tumors in which nischarin is predicted to be a positive prognostic marker.

Abstract 1339: Pre-clinical development of IAMA-004, a tri-specific antibody targeting innate immune receptors and tumor targets

Abstract Immune check-point inhibitor (ICI) such as anti-PD1 or anti-PDL1 antibody, which enhances the adaptive immunity via re-energizing exhausted T cells, has become the foundational therapy for many cancers. However, due to variety of other immunosuppressive tumor microenvironments, it is efficacious only in 15-30% of the patients. It is well known both the innate immunity and the adaptive immunity are required for full control of cancer growth. Thus, therapeutics harnessing the innate immunity will be complementary to ICI and improve the cancer response rate when used in combination. Currently therapeutics harnessing the innate immunity mainly involve bispecific antibodies with one arm targeting tumor antigen and one arm connecting to innate effector cells such as NK cells or macrophages, represented by CD30-CD16a bispecific and Her2-CD47 bispecific respectively. Considering that cancer patient’s immune status are heterogenous, varying from T cell exhaustion, macrophage disfunction (M2 bias), Treg cell presence to NK cell deficiencies, it would be advantageous to combine several innate immunity enhancers into one therapeutic molecule. Here we describe a long-acting tri-specific antibody termed IAMA-004 that targets Her2 as the primary target and CD47 and CD16a as effector cell engagers. CD47 is also a co-target on some tumor cells (CD47-Her2 double positive tumors). We have characterized this molecule both in vitro and in vivo. The in vitro experiments tested the molecule’s ability to kill Her2 high, Her2 low and Her2 negative tumor cell lines including BT-474, SK-OV-3, NCI-N87, OE19, HCC1954, MDA-MB-231, MDA-MB-468, in human PBMC ADCC assays with DS-8201 and Trastuzmab as the comparator molecules. In all of these ADCC experiments, IAMA-004 showed superior tumor cell killing activities to those mediated by DS-8201 or Trastuzmab. When combined with IAMA-005 (a Fc-IL2-IFN-α fusion cytokine), the tumor cell killing activities were dramatically increased. In addition, IAMA-004 was also tested in patient-derived Ex-Vivo fluids (one malignant pleural effusion and one malignant asities) and demonstrated tumor cell killing efficacies; and the killing activity could be attributed to the specific arms of the molecule. These results suggest that it is feasible to combine more than one innate engager in one molecule to carry out specific functions in the heterogeneous immune status for the treatment of advanced cancer patients. Citation Format: Liming Liu, Zhen Han, Yang Fan, Qi Pan. Pre-clinical development of IAMA-004, a tri-specific antibody targeting innate immune receptors and tumor targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1339.

Abstract 5216: Peripheral T cell receptor repertoire diversity is associated with outcome in bladder cancer

Abstract Bladder cancer is the sixth most common cancer overall, and treatment often involves removal of the bladder, which comes with a significant reduction in quality of life. Within this cancer type, an easily applicable prognostic biomarker may have clinical utility, potentially stratifying patients into bladder-sparing treatments. Expansion of T cell populations targeting cancer-specific neoantigens is an early response to malignancy. To investigate if the T cell receptor (TCR) repertoire could serve as a biomarker for cancer progression, we analyzed the TCR landscape in a cohort of 119 patients with muscle-invasive bladder cancer, treated with neoadjuvant chemotherapy before undergoing radical cystectomy. Peripheral and tumor TCR repertoires were produced using amplicon-based sequencing of the TCR beta chain. Additionally, T cell fraction was determined from whole exome sequencing data using TcellExTRECT, and latent viral DNA was investigated in plasma whole genome sequencing data using Kraken2. Antigen targets were estimated using GLIPH2. To explore the T cell repertoire subtypes, single-cell sequencing was performed on four fresh blood samples. In pre-treatment peripheral blood, low-diversity TCR repertoires were associated with worse survival (HR=2.3, p=0.024). Particularly poor outcome was observed in a subset of patients with both low TCR diversity and low fraction of circulating T cells (HR=4.7, p=5e-4). Low-diversity repertoires were dominated by expanded T cell clones. TCR target annotation revealed that expanded T cell clones disproportionately targeted latent viral infections (p=2e-13), and cytomegalovirus DNA detection was strongly associated with decreased TCR diversity (p=5e-5). Additionally, tumor TCR sequencing revealed that expanded clones were rarely found in the tumor. Single-cell sequencing of peripheral blood found that most expanded clones consisted of cytotoxic T cells, while non-expanded clones mostly consisted of naive T cells. This indicates that low TCR diversity may represent a contraction of the naive T cell compartment, resulting in reduced immune competence. Finally, analysis of patient-matched longitudinal samples revealed that chemotherapy and cystectomy reduced TCR diversity in patients with high pre-treatment diversity (p=0.001), indicating that treatment negatively affected the immune system in the most immune-competent patients. Our results suggest that both low TCR diversity and low T cell fraction represent decreased immune competency. This could be associated with an elevated risk of progression due to a reduced ability to control cancer growth and limit systemic cancer cell dissemination. These findings underline that immune health is an important factor during malignant disease, even when patients are not treated with immunotherapies. Therefore, improving immune health could be a potential future goal for cancer treatment and prevention. Citation Format: Asbjørn Kjær, Nanna Kristjánsdóttir, Iver Nordentoft, Randi Istrup Juul, Karin Birkenkamp-Demtröder, Johanne Ahrenfeldt, Darren Hodgson, Christopher Abbosh, Hugo JWL Aerts, Mads Agerbæk, Jørgen Bjerggaard Jensen, Nicolai J Birkbak, Lars Dyrskjøt. Peripheral T cell receptor repertoire diversity is associated with outcome in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5216.

Fractional Modeling of Cancer with Mixed Therapies.

Cancer is the biggest cause of mortality globally, with approximately 10 million fatalities expected by 2020, or about one in every six deaths. Breast, lung, colon, rectum, and prostate cancers are the most prevalent types of cancer. In this work, fractional modeling is presented which describes the dynamics of cancer treatment with mixed therapies (immunotherapy and chemotherapy). Mathematical models of cancer treatment are important to understand the dynamical behavior of the disease. Fractional models are studied considering immunotherapy and chemotherapy to control cancer growth at the level of cell populations. The models consist of the system of fractional differential equations (FDEs). Fractional term is defined by Caputo fractional derivative. The models are solved numerically by using Adams-Bashforth-Moulton method. For all fractional models the reasonable range of fractional order is between β = 0.6 and β = 0.9. The equilibrium points and stability analysis are presented. Moreover, positivity and boundedness of the solution are proved. Furthermore, a graphical representation of cancerous cells, immunotherapy and chemotherapy is presented to understand the behaviour of cancer treatment. At the end, a curve fitting procedure is presented which may help medical practitioners to treat cancer patients.

Decoupled neoantigen cross-presentation by dendritic cells limits anti-tumor immunity against tumors with heterogeneous neoantigen expression.

Cancer immunotherapies, in particular checkpoint blockade immunotherapy (CBT), can induce control of cancer growth, with a fraction of patients experiencing durable responses. However, the majority of patients currently do not respond to CBT and the molecular determinants of resistance have not been fully elucidated. Mounting clinical evidence suggests that the clonal status of neoantigens (NeoAg) impacts the anti-tumor T cell response. High intratumor heterogeneity (ITH), where the majority of NeoAgs are expressed subclonally, is correlated with poor clinical response to CBT and poor infiltration with tumor-reactive T cells. However, the mechanism by which ITH blunts tumor-reactive T cells is unclear. We developed a transplantable murine lung cancer model to characterize the immune response against a defined set of NeoAgs expressed either clonally or subclonally to model low or high ITH, respectively. Here we show that clonal expression of a weakly immunogenic NeoAg with a relatively strong NeoAg increased the immunogenicity of tumors with low but not high ITH. Mechanistically we determined that clonal NeoAg expression allowed cross-presenting dendritic cells to acquire and present both NeoAgs. Dual NeoAg presentation by dendritic cells was associated with a more mature DC phenotype and a higher stimulatory capacity. These data suggest that clonal NeoAg expression can induce more potent anti-tumor responses due to more stimulatory dendritic cell:T cell interactions. Therapeutic vaccination targeting subclonally expressed NeoAgs could be used to boost anti-tumor T cell responses.

PIK3R3 is upregulated in liver cancer and activates Akt signaling to control cancer growth by regulation of CDKN1C and SMC1A.

Liver cancer is a highly malignant disease and the third leading cause of cancer death worldwide. Abnormal activation of PI3K/Akt signaling is common in cancer, but whether phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3) plays a role in liver cancer is largely unexplored. We determined the expression of PIK3R3 in liver cancer by using TCGA data and our clinical samples and knocked it down by siRNA or overexpressing it by the lentivirus vector system. We also investigated the function of PIK3R3 by colony formation, 5-Ethynyl-2-Deoxyuridine, flow cytometry assay, and subcutaneous xenograft model. The downstream of PIK3R3 was explored by RNA sequence and rescue assays. We found that PIK3R3 was significantly upregulated in liver cancer and correlated with prognosis. PIK3R3 promoted liver cancer growth in vitro and in vivo by controlling cell proliferation and cell cycle. RNA sequence revealed that hundreds of genes were dysregulated upon PIK3R3 knockdown in liver cancer cells. CDKN1C, a cyclin-dependent kinase inhibitor, was significantly upregulated by PIK3R3 knockdown, and CDKN1C siRNA rescued the impaired tumor cell growth. SMC1A was partially responsible for PIK3R3 regulated function, and SMC1A overexpression rescued the impaired tumor cell growth in liver cancer cells. Immunoprecipitation demonstrated there is indirect interaction between PIK3R3 and CNKN1C or SMC1A. Importantly, we verified that PIK3R3-activated Akt signaling determined the expression of CDKN1C and SMC1A, two downstream of PIK3R3 in liver cancer cells. PIK3R3 is upregulated in liver cancer and activates Akt signaling to control cancer growth by regulation of CDNK1C and SMC1A. Targeting PIK3R3 could be a promising treatment strategy for liver cancer that deserves further investigation.

Tumor lysis syndrome promotes cancer chemoresistance and relapse through AMPK inhibition.

Cancer is a disease caused when cells divide uncontrollably and spread into surrounding tissues. There are different therapeutic modalities that control cancer growth, of which surgery, chemotherapy, and radiotherapy. Chemotherapy is a cancer treatment approach in which medications are used to inhibit cell proliferation and tumor multiplication, thus avoiding invasion and metastasis and thus eradicate cancer. One of the common complications associated with cancer chemotherapy is rapid lysis of expanding tumor cells, known as tumor lysis syndrome (TLS). TLS is associated with number of metabolic changes such as hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia. Among the consequences of hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia is the inhibition of 5' AMP-activated protein kinase (AMPK). Inhibition of AMPK induced different cancer chemo-resistance mechanisms such as cancer stem cells (CSCs), p-glycoproteins, Octamer-binding transcription factor 4 (OCT-4), homeobox protein NANOG, Krüppel-like factor 4 (KLF4) and immune microenvironment and thus leads to poor response to chemotherapy and even relapses after treatment. Our review aims to uncover new mechanisms underlying the metabolic consequences of tumor lysis on AMPK in tumor microenvironment. In this review, we also investigated the effect of AMPK on different cancer chemo-resistance mechanisms such as cancer stem cells, p-glycoproteins, OCT-4, NANOG, KLF4 and immune microenvironment.

Non-bioenergetic roles of mitochondrial GPD2 promote tumor progression.

Rationale: Despite growing evidence for mitochondria's involvement in cancer, the roles of specific metabolic components outside the respiratory complex have been little explored. We conducted metabolomic studies on mitochondrial DNA (mtDNA)-deficient (ρ0) cancer cells with lower proliferation rates to clarify the undefined roles of mitochondria in cancer growth. Methods and results: Despite extensive metabolic downregulation, ρ0 cells exhibited high glycerol-3-phosphate (G3P) level, due to low activity of mitochondrial glycerol-3-phosphate dehydrogenase (GPD2). Knockout (KO) of GPD2 resulted in cell growth suppression as well as inhibition of tumor progression in vivo. Surprisingly, this was unrelated to the conventional bioenergetic function of GPD2. Instead, multi-omics results suggested major changes in ether lipid metabolism, for which GPD2 provides dihydroxyacetone phosphate (DHAP) in ether lipid biosynthesis. GPD2 KO cells exhibited significantly lower ether lipid level, and their slower growth was rescued by supplementation of a DHAP precursor or ether lipids. Mechanistically, ether lipid metabolism was associated with Akt pathway, and the downregulation of Akt/mTORC1 pathway due to GPD2 KO was rescued by DHAP supplementation. Conclusion: Overall, the GPD2-ether lipid-Akt axis is newly described for the control of cancer growth. DHAP supply, a non-bioenergetic process, may constitute an important role of mitochondria in cancer.

The transcription factor IRF2 drives interferon-mediated CD8+ T cell exhaustion to restrict anti-tumor immunity

Type I and II interferons (IFNs) stimulate pro-inflammatory programs that are critical for immune activation, but also induce immune-suppressive feedback circuits that impede control of cancer growth. Here, we sought to determine how these opposing programs are differentially induced. We demonstrated that the transcription factor interferon regulatory factor 2 (IRF2) was expressed by many immune cells in the tumor in response to sustained IFN signaling. CD8+ Tcell-specific deletion of IRF2 prevented acquisition of the Tcell exhaustion program within the tumor and instead enabled sustained effector functions that promoted long-term tumor control and increased responsiveness to immune checkpoint and adoptive cell therapies. The long-term tumor control by IRF2-deficient CD8+ Tcells required continuous integration of both IFN-I and IFN-II signals. Thus, IRF2 is a foundational feedback molecule that redirects IFN signals to suppress Tcell responses and represents a potential target to enhance cancer control.

Copper-Dependent Kinases and Their Role in Cancer Inception, Progression and Metastasis.

In recent years, copper function has been expanded beyond its consolidated role as a cofactor of enzyme catalysis. Recent papers have demonstrated a new dynamic role for copper in the regulation of cell signaling pathways through direct interaction with protein kinases, modulating their activity. The activation of these pathways is exacerbated in cancer cells to sustain the different steps of tumor growth and dissemination. This review will focus on a novel proposed role for the transition metal copper as a regulator of cell signaling pathways through direct interaction with known protein kinases, which exhibit binding domains for this metal. Activation of these pathways in cancer cells supports both tumor growth and dissemination. In addition to the description of the results recently reported in the literature on the subject, relevance will be given to the possibility of controlling the cellular levels of copper and its homeostatic regulators. Overall, these findings may be of central relevance in order to propose copper and its homeostatic regulators as possible targets for novel therapies, which may act synergistically to those already existing to control cancer growth and dissemination.

Effects of smart voice control devices on children: current challenges and future perspectives

Interleukin (IL)-10 is expressed in many solid tumours and plays an ambiguous role in controlling cancer growth and metastasis. In order to determine whether IL-10 is involved in tumour progression...

Growth hormone receptor antagonism downregulates ATP-binding cassette transporters contributing to improved drug efficacy against melanoma and hepatocarcinoma in vivo

Knockdown of GH receptor (GHR) in melanoma cells in vitro downregulates ATP-binding cassette-containing (ABC) transporters and sensitizes them to anti-cancer drug treatments. Here we aimed to determine whether a GHR antagonist (GHRA) could control cancer growth by sensitizing tumors to therapy through downregulation of ABC transporters in vivo. We intradermally inoculated Fluc-B16-F10 mouse melanoma cells into GHA mice, transgenic for a GHR antagonist (GHRA), and observed a marked reduction in tumor size, mass and tumoral GH signaling. Moreover, constitutive GHRA production in the transgenic mice significantly improved the response to cisplatin treatment by suppressing expression of multiple ABC transporters and sensitizing the tumors to the drug. We confirmed that presence of a GHRA and not a mere absence of GH is essential for this chemo-sensitizing effect using Fluc-B16-F10 allografts in GH knockout (GHKO) mice, where tumor growth was reduced relative to that in GH-sufficient controls but did not sensitize the tumor to cisplatin. We extended our investigation to hepatocellular carcinoma (HCC) using human HCC cells in vitro and a syngeneic mouse model of HCC with Hepa1-6 allografts in GHA mice. Gene expression analyses and drug-efflux assays confirm that blocking GH significantly suppresses the levels of ABC transporters and improves the efficacy of sorafenib towards almost complete tumor clearance. Human patient data for melanoma and HCC show that GHR RNA levels correlate with ABC transporter expression. Collectively, our results validate in vivo that combination of a GHRA with currently available anti-cancer therapies can be effective in attacking cancer drug resistance.

P1435: PRECLINICAL EVALUATION OF ZILOVERTAMAB-BASED ANTI-ROR1 CHIMERIC ANTIGEN RECEPTORS IN NK AND T CELLS

Background: The receptor tyrosine kinase-like orphan receptor ROR1 is a promising target for immunotherapies of many cancers, including mantle cell lymphoma, diffuse large B-cell lymphoma, B-cell acute lymphocytic leukemia and chronic lymphocytic leukemia. Normally only expressed during embryonic development and only minimally, if at all, in adult normal tissues, ROR1 is overexpressed on malignant cells. Zilovertamab is a monoclonal antibody binding ROR1 that is currently in Phase 1/2 clinical trials. The antibody blocks survival signals mediated by Wnt5a via the ROR1 receptor. A different approach is the use of the antigen binding domain of the antibody in chimeric antigen receptors (CARs) expressed in NK or T cells to induce cellular cytotoxicity against ROR1-expressing cancer cells. Aims: This study aimed to evaluate different CAR designs in NK cells and T cells for cytotoxicity and cytokine production in vitro and control of cancer growth in a murine in vivo model. Methods: Two CARs using different linkers between the single chain antibody fragment (scFv) and the transmembrane domain were designed and cloned into lentiviral vectors. The two constructs were expressed in the cell line NK92 and the cells’ response against ROR1-positive and negative cancer cell lines was measured by degranulation and interferon-γ production. The construct that showed a stronger activation was tested in an in vivo model. Immune deficient NSG mice were injected with ROR1-positive JEKO-1 cells transgenic for luciferase. The cancer cell burden was monitored by intravital imaging. When cancer cell growth was established, the mice received either 1, 3, or 9 x 106 human T cells expressing the CAR or untransduced T cells. Results: NK92 cells expressing either of the two CARs showed enhanced degranulation and IFN-γ production in response to the ROR1-expressing cancer cell lines RPMI 8226 and JEKO-1. NK cells expressing the CAR containing the shorter linker between the scFv and the transmembrane domain exhibited higher activation levels. Primary human T cells expressing this CAR construct demonstrated degranulation and cytokine production during co-incubation with the ROR1-expressing JEKO-1 cell line but not the ROR1-negative Jurkat cell line. Injection of anti-ROR1 human CAR-T cells into NSG mice with established cancer growth greatly reduced the cell burden of JEKO-1 while untransduced T cells were unable to control cancer cell growth. Summary/Conclusion: The zilovertamab-based CAR tested in this study enhances the NK cell response towards ROR1-expressing cancer cells and enables T cells to clear fast-growing cancer cells in an in vivo model. These findings support the development of anti-ROR1 cell therapies for the potential treatment of ROR1-positive hematological malignancies.

HF01-13 FROM TORTURE TO THERAPY: THE HISTORY OF HUMAN CASTRATION

You have accessJournal of UrologyCME1 May 2022HF01-13 FROM TORTURE TO THERAPY: THE HISTORY OF HUMAN CASTRATION Antonio Nacchia, Riccardo Lombardo, Cosimo De Nunzio, and Andrea Tubaro Antonio NacchiaAntonio Nacchia More articles by this author , Riccardo LombardoRiccardo Lombardo More articles by this author , Cosimo De NunzioCosimo De Nunzio More articles by this author , and Andrea TubaroAndrea Tubaro More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002541.13AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Castration is any action, surgical or chemical, by which an individual loses the use of the gonads, particularly testicles. Surgical castration consists in bilateral orchiectomy and chemical castration uses pharmaceutical drugs to deactivate the testes. Human castration is a practice known from Sumerian time as cruel torture. In history, it has been a religious practice or instrument to obtain eunuch slaves or white voices. Aim of our study was to explore the history of human castration. METHODS: A literature review on human castration was performed through Medline, PubMed and Google Scholar, searching words “castration”, “orchiectomy” and “androgen deprivation”. RESULTS: The earliest records for intentional human castration to produce eunuchs are from the Sumerian city of Lagash in the 21st century BC. Ancient Greeks and ancient Romans used it to produce eunuch slaves. During Byzantine Empire, it was considered such as a punishment. In Arabian countries castration started to be used to obtain faithful harem guardians since 750 AD and then, during the Ottoman Empire, the Imperial Harem was a powerful institution of the Sultan. From the late 16th century castration was carried out in Italy to preserve the unbroken male voice into adult life. In 1941 Huggins and Hodges demonstrated control of prostate cancer growth rate by androgens and showed that there is no better way to achieve temporary control of prostate cancer growth than androgen deprivation (AD). The earliest method of AD is represented by the bilateral orchiectomy, which means a definitive therapy for the patient. In 1944 treatment with Diethylstilbestrol was described as to the first method of reversible castration. In 1979 Schally et al showed that advanced prostate cancer patients treated with daily doses of LHRH agonists experienced a 75% decrease in serum testosterone levels and a marked reduction in cancer-associated bone pain. Medical castration by means of medrossiprogesterone acetate or cyproterone acetate is also used for convicted rapist or sex offenders in some countries. Although more expensive, medical castration is nowadays the standard considering its hypothetical reversible effect and the psychological trauma related to surgery. CONCLUSIONS: The possibility to change male habitus through surgical castration has been evident since the 11th century BC and used to punish or to create specific workers such as eunuchs or singers. Just only in the last century the role of surgical castration has been associated with prostate cancer treatment and LHRH agonist and antagonist have become the new standard to induce castration. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e216 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Antonio Nacchia More articles by this author Riccardo Lombardo More articles by this author Cosimo De Nunzio More articles by this author Andrea Tubaro More articles by this author Expand All Advertisement PDF DownloadLoading ...

Surgery, Chemotherapy and Radiotherapy May Promote Cancer Growth Speeds and Shorten Patient Lives

Medicine fails to find predictable cures for cancer in more than a century, and we explored the feasibility of controlling cancer growth speed by using lifestyle factors. After conducting an extensive literature review, we conducted simulations for cancer growth courses to see the feasibility of controlling cancer growth speeds. We found that (1) medical treatments are often accompanied by three to four lethal factors: treatment side-effects, emotional distress, and chronic stress, reduced exercises and physical inactivity, and excessive nutrition in some cases; (2) clinical trial exaggerates treatments short-term benefits and underestimates the slow-delivering adverse side effects as a result of statistical averaging, interfering effects of personal lifestyle factors and insufficient follow-up times; (3) the benefits of medical treatments are limited by chain comparisons, where surgery may work as a negative standard relative to the best alternatives for resolving cancer; (4) the strategy of destroying the tumor or killing all cancer cells is unworkable; (5) medical treatments can turn natural cancer growth curve into approximately doubly exponential curve; (6) multiple-factor non-medical measures are potentially much more powerful than medical treatments in controlling cancer growth and metastasis speeds; and (7) cancer early diagnosis and over treatments are unwise strategies in light of discoveries. Based on huge increases in cancer growth rate constants, substantial loss of vital organ functional capacity, and severe systemic aging-like cellular damages, we concluded that medical treatments may promote cancer growth and metastasis speeds and shorten patient lives in most situations, and the claimed benefits are caused by triple biases of clinical trials. By using the same method to explore how several lifestyle factors affect cancer growth rates, we concluded that the better strategy for ending the global cancer epidemic in the future is changing caner treatment strategy from killing cancer cells to slowing down cancer growth rates by using various lifestyle factors in combination. This study in part explains why cancer can self-resolve.

M6A RNA Methylation Regulates Histone Ubiquitination to Support Cancer Growth and Progression.

RNA demethylase ALKBH5 upregulates USP22 and RNF40 to inhibit histone H2A ubiquitination and induces expression of key replication and DNA repair-associated genes, driving osteosarcoma progression.

Imiquimod-gemcitabine nanoparticles harness immune cells to suppress breast cancer

Monotherapy with a single chemotherapeutic regimen has met with significant hurdles in terms of clinical efficacy. The complexity of cancer accentuates the need for an alternative approach with a combination of two or more therapeutic regimens to win the battle. However, it is still a challenge to develop a successful combination of drugs with high efficiency and low toxicity to control cancer growth. While gemcitabine monotherapy remains a choice of standard treatment for advanced breast cancer, the approach has not prolonged the median survival time of metastatic breast cancer patients. Here, we report a hyaluronic acid (HA)-based drug combination of gemcitabine (GEM) with imiquimod (IMQ) to stimulate immune cells for anticancer activity. Treatment of the drug combination (IMQ-HA-GEM) showed enhanced anticancer activity against 4T1 breast tumor cells in vitro. Our study with a microfluidics-based 3D, compartmentalized cancer model showed that infiltration of THP-1 monocytes occurred particularly at the site of cancer cells treated with IMQ-HA-GEM. Moreover, IMQ-HA-GEM significantly suppressed the volume of 4T1 breast tumor of mice in vivo. Flow cytometry study displayed a significantly higher activation of CD11b+ immune cells in the blood of mice treated with IMQ-HA-GEM, whereas immunohistochemistry study revealed greater prevalence of CD68+ tumor-associated macrophages in the tumor. Histological examination of isolated tumors of mice treated with IMQ-HA-GEM further confirmed the efficacy of drug combination on cancer cells. This study supports the conclusion that imiquimod potentiates the effect of gemcitabine by activating immune cells to suppress tumors in the form of combination nanoparticles.