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1.
Cancers (Basel) ; 13(6)2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33801965

RESUMO

The Kirsten rat sarcoma viral oncogene homolog (KRAS) is mutated in approximately 25% of all human cancers and is known to be a major player promoting and maintaining tumorigenesis through the RAS/MAPK pathway. Over the years, a large number of studies have identified strategies at different regulatory levels to tackle this 'difficult-to-target' oncoprotein. Yet, the most ideal strategy to overcome KRAS and its downstream effects has yet to be uncovered. This review summarizes the role of KRAS activating mutations in multiple cancer types as well as the key findings for potential strategies inhibiting its oncogenic behavior. A comprehensive analysis of the different pathways and mechanisms associated with KRAS activity in tumors will ultimately pave the way for promising future work that will identify optimum therapeutic strategies.

2.
J Immunol ; 206(8): 1966-1975, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33722878

RESUMO

Inflammation has long been associated with cancer initiation and progression; however, how inflammation causes immune suppression in the tumor microenvironment and resistance to immunotherapy is not well understood. In this study, we show that both innate proinflammatory cytokine IL-1α and immunotherapy-induced IL-1α make melanoma resistant to immunotherapy. In a mouse melanoma model, we found that tumor size was inversely correlated with response to immunotherapy. Large tumors had higher levels of IL-1α, Th2 cytokines, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), and regulatory T cells but lower levels of IL-12, Th1 cytokines, and activated T cells. We found that therapy with adenovirus-encoded CD40L (rAd.CD40L) increased tumor levels of IL-1α and PMN-MDSCs. Blocking the IL-1 signaling pathway significantly decreased rAd.CD40L-induced PMN-MDSCs and their associated PD-L1 expression in the tumor microenvironment and enhanced tumor-specific immunity. Similarly, blocking the IL-1 signaling pathway improved the antimelanoma activity of anti-PD-L1 Ab therapy. Our study suggests that blocking the IL-1α signaling pathway may increase the efficacy of immunotherapies against melanoma.

3.
Gastroenterology ; 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33745946

RESUMO

BACKGROUND & AIMS: Understanding the mechanisms by which tumors adapt to therapy is critical for developing effective combination therapeutic approaches to improve clinical outcomes for patients with cancer. METHODS: To identify promising and clinically actionable targets for managing colorectal cancer (CRC), we conducted a patient-centered functional genomics platform that includes approximately 200 genes and paired this with a high-throughput drug screen that includes 262 compounds in four patient-derived xenografts (PDXs) from patients with CRC. RESULTS: Both screening methods identified exportin 1 (XPO1) inhibitors as drivers of DNA damage-induced lethality in CRC. Molecular characterization of the cellular response to XPO1 inhibition uncovered an adaptive mechanism that limited the duration of response in TP53-mutated, but not in TP53-wild-type CRC models. Comprehensive proteomic and transcriptomic characterization revealed that the ATM/ATR-CHK1/2 axes were selectively engaged in TP53-mutant CRC cells upon XPO1 inhibitor treatment and that this response was required for adapting to therapy and escaping cell death. Administration of KPT-8602, an XPO1 inhibitor, followed by AZD-6738, an ATR inhibitor, resulted in dramatic antitumor effects and prolonged survival in TP53-mutant models of CRC. CONCLUSIONS: Our findings anticipate tremendous therapeutic benefit and support the further evaluation of XPO1 inhibitors, especially in combination with DNA damage checkpoint inhibitors, to elicit an enduring clinical response in patients with CRC harboring TP53 mutations.

4.
Cancer Discov ; 11(5): 1024-1039, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33722796

RESUMO

Immunotherapeutic manipulation of the antitumor immune response offers an attractive strategy to target genomic instability in cancer. A subset of tumor-specific somatic mutations can be translated into immunogenic and HLA-bound epitopes called neoantigens, which can induce the activation of helper and cytotoxic T lymphocytes. However, cancer immunoediting and immunosuppressive mechanisms often allow tumors to evade immune recognition. Recent evidence also suggests that the tumor neoantigen landscape extends beyond epitopes originating from nonsynonymous single-nucleotide variants in the coding exome. Here we review emerging approaches for identifying, prioritizing, and immunologically targeting personalized neoantigens using polyvalent cancer vaccines and T-cell receptor gene therapy. SIGNIFICANCE: Several major challenges currently impede the clinical efficacy of neoantigen-directed immunotherapy, such as the relative infrequency of immunogenic neoantigens, suboptimal potency and priming of de novo tumor-specific T cells, and tumor cell-intrinsic and -extrinsic mechanisms of immune evasion. A deeper understanding of these biological barriers could help facilitate the development of effective and durable immunotherapy for any type of cancer, including immunologically "cold" tumors that are otherwise therapeutically resistant.

5.
Clin Cancer Res ; 27(6): 1663-1670, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33414133

RESUMO

PURPOSE: AT-rich interactive domain 1A (ARID1A) is commonly mutated in colorectal cancer, frequently resulting in truncation and loss of protein expression. ARID1A recruits MSH2 for mismatch repair during DNA replication. ARID1A deficiency promotes hypermutability and immune activation in preclinical models, but its role in patients with colorectal cancer is being explored. EXPERIMENTAL DESIGN: The DNA sequencing and gene expression profiling of patients with colorectal cancer were extracted from The Cancer Genome Atlas and MD Anderson Cancer Center databases, with validation utilizing external databases, and correlation between ARID1A and immunologic features. IHC for T-cell markers was performed on a separate cohort of patients. RESULTS: Twenty-eight of 417 patients with microsatellite stable (MSS) colorectal cancer (6.7%) had ARID1A mutation. Among 58 genes most commonly mutated in colorectal cancer, ARID1A mutation had the highest increase with frameshift mutation rates in MSS cases (8-fold, P < 0.001). In MSS, ARID1A mutation was enriched in immune subtype (CMS1) and had a strong correlation with IFNγ expression (Δz score +1.91, P < 0.001). Compared with ARID1A wild-type, statistically significant higher expression for key checkpoint genes (e.g., PD-L1, CTLA4, and PDCD1) and gene sets (e.g., antigen presentation, cytotoxic T-cell function, and immune checkpoints) was observed in mutant cases. This was validated by unsupervised differential expression of genes related to immune response and further confirmed by higher infiltration of T cells in IHC of tumors with ARID1A mutation (P = 0.01). CONCLUSIONS: The immunogenicity of ARID1A-mutant cases is likely due to an increased level of neoantigens resulting from increased tumor mutational burden and frameshift mutations. Tumors with ARID1A mutation may be more susceptible to immune therapy-based treatment strategies and should be recognized as a unique molecular subgroup in future immune therapy trials.

6.
Mol Cancer Res ; 19(4): 667-677, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33380466

RESUMO

Ubiquitin specific peptidase 18 (USP18), previously known as UBP43, is the IFN-stimulated gene 15 (ISG15) deconjugase. USP18 removes ISG15 from substrate proteins. This study reports that USP18-null mice (vs. wild-type mice) exhibited lower lipolysis rates, altered fat to body weight ratios, and cold sensitivity. USP18 is a regulator of lipid and fatty acid metabolism. Prior work established that USP18 promotes lung tumorigenesis. We sought to learn whether this occurs through altered lipid and fatty acid metabolism. Loss of USP18 repressed adipose triglyceride lipase (ATGL) expression; gain of USP18 expression upregulated ATGL in lung cancer cells. The E1-like ubiquitin activating enzyme promoted ISG15 conjugation of ATGL and destabilization. Immunoprecipitation assays confirmed that ISG15 covalently conjugates to ATGL. Protein expression of thermogenic regulators was examined in brown fat of USP18-null versus wild-type mice. Uncoupling protein 1 (UCP1) was repressed in USP18-null fat. Gain of USP18 expression augmented UCP1 protein via reduced ubiquitination. Gain of UCP1 expression in lung cancer cell lines enhanced cellular proliferation. UCP1 knockdown inhibited proliferation. Beta-hydroxybutyrate colorimetric assays performed after gain of UCP1 expression revealed increased cellular fatty acid beta-oxidation, augmenting fatty acid beta-oxidation in Seahorse assays. Combined USP18, ATGL, and UCP1 profiles were interrogated in The Cancer Genome Atlas. Intriguingly, lung cancers with increased USP18, ATGL, and UCP1 expression had an unfavorable survival. These findings reveal that USP18 is a pharmacologic target that controls fatty acid metabolism. IMPLICATIONS: USP18 is an antineoplastic target that affects lung cancer fatty acid metabolism.

7.
Mol Cancer Ther ; 20(3): 500-511, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33361272

RESUMO

Immune-checkpoint inhibitors and adoptive tumor-infiltrating lymphocyte (TIL) therapies have profoundly improved the survival of patients with melanoma. However, a majority of patients do not respond to these agents, and many responders experience disease relapse. Although numerous innovative treatments are being explored to offset the limitations of these agents, novel therapeutic combinations with immunotherapies have the potential to improve patient responses. In this study, we evaluated the antimelanoma activity of immunotherapy combinations with Telaglenastat (CB-839), a potent glutaminase inhibitor (GLSi) that has favorable systemic tolerance. In in vitro TIL:tumor coculture studies, CB-839 treatment improved the cytotoxic activity of autologous TILs on patient-derived melanoma cells. CB-839 treatment decreased the conversion of glutamine to alpha-ketoglutarate (αKGA) more potently in tumor cells versus TILs in these cocultures. These results suggest that CB-839 may improve immune function in a tumor microenvironment by differentially altering tumor and immune cell metabolism. In vivo CB-839 treatment activated melanoma antigen-specific T cells and improved their tumor killing activity in an immune-competent mouse model of adoptive T-cell therapy. Additionally, the combination of CB-839 with anti-PD1 or anti-CTLA4 antibodies increased tumor infiltration by effector T cells and improved the antitumor activity of these checkpoint inhibitors in a high mutation burden mouse melanoma model. Responsiveness to these treatments was also accompanied by an increase of interferon gamma (IFNγ)-associated gene expression in the tumors. Together, these results provide a strong rationale for combining CB-839 with immune therapies to improve efficacy of these treatments against melanoma.

8.
Mol Cancer Res ; 19(3): 395-402, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33323389

RESUMO

Prognosis for patients with metastatic bladder carcinoma (mBC) remains limited and in need of novel therapies. We retrospectively analyzed medical records of 43 patients with platinum-refractory metastatic bladder cancer (mBC) who participated in one or more phase I trials of various investigational therapies. Patients' tumors or circulating tumor DNA were analyzed by next-generation sequencing. The median progression-free survival was 4.2 months, the median overall survival was 9.6 months, and the overall response rate was 17.5%. TP53, ERBB2, PI3KCA, FGFR3, and ARID1A alterations were detected in 66%, 29%, 27%, 24%, and 22% of all patients, respectively. Alterations in FGFR3 were almost mutually exclusive of TP53. More than half (64%) of patients with an FGFR alt received an FGFR inhibitor, 67% of which achieved disease control. Among patients with urothelial carcinoma histology, those harboring a TP53 alteration had a shorter median progression-free survival (PFS) compared with those whose tumors carry wild-type TP53. The reverse relationship was observed in patients harboring an FGFR alteration. IMPLICATIONS: Patients with platinum-refractory mBC derive clinical benefit from participating in early-phase clinical trials and their survival outcomes correlate with the genetic profile of the tumor. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/3/395/F1.large.jpg.

9.
Mol Cancer Ther ; 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33277443

RESUMO

Cyclin dependent kinase 2 (CDK2) antagonism inhibits clustering of excessive centrosomes at mitosis, causing multipolar cell division and apoptotic death. This is called anaphase catastrophe. To establish induced anaphase catastrophe as a clinically-tractable anti-neoplastic mechanism, induced anaphase catastrophe was explored in different aneuploid cancers after treatment with CYC065 (Cyclacel), a CDK2/9 inhibitor. Anti-neoplastic activity was studied in pre-clinical models. CYC065-treatment augmented anaphase catastrophe in diverse cancers including lymphoma, lung, colon and pancreatic cancers, despite KRAS oncoprotein expression. Anaphase catastrophe was a broadly active anti-neoplastic mechanism. Reverse phase protein arrays (RPPAs) revealed that along with known CDK2/9 targets, focal adhesion kinase (FAK) and Src phosphorylation that regulate metastasis were each repressed by CYC065-treatment. Intriguingly, CYC065-treatment decreased lung cancer metastases in in vivo murine models. CYC065-treatment also significantly reduced the rate of lung cancer growth in syngeneic murine and patient-derived xenograft (PDX) models independent of KRAS oncoprotein expression. Immunohistochemical analysis of CYC065-treated lung cancer PDX models confirmed repression of proteins highlighted by RPPAs, implicating them as indicators of CYC065 anti-tumor response. Phospho-histone H3 staining detected anaphase catastrophe in CYC065-treated PDXs. Thus, induced anaphase catastrophe after CYC065-treatment can combat aneuploid cancers despite KRAS oncoprotein expression. These findings should guide future trials of this novel CDK2/9 inhibitor in the cancer clinic.

10.
Cancers (Basel) ; 12(11)2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33227959

RESUMO

This Special Issue on "Single-cell Data Science" aims to highlight recent advances in the area of single-cell sequencing technologies and data analytics [...].

11.
ESMO Open ; 5(6)2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33229506

RESUMO

BACKGROUND: For patients with metastatic renal cell carcinoma (mRCC) who progress on standard-of-care therapies, there is an unmet need for novel treatments. Phase I clinical trials are designed to test the safety, toxicity and optimal dosing of novel agents. Herein, we analysed the outcomes of patients with mRCC enrolled in phase I trials and assess the utility of prognostic scores. METHODS: Patients with all histologies of mRCC were included if they received treatment on a phase I clinical trial at MD Anderson Cancer Center (MDACC). Survival outcomes were calculated using Cox proportional hazard model. Prognostic value of the International Metastatic RCC Database Consortium (IMDC), Royal Marsden Hospital (RMH) and MDACC scores was assessed using the likelihood ratio (LR) χ2 test and the c-index. RESULTS: Among 82 patients with mRCC who received treatment, 21 patients participated in more than one trial, resulting in 106 trial participants (TP). Median prior therapies was two. For all TPs, median overall survival (OS) was 31.2 months, progression-free survival (PFS) was 5.9 months and objective response rate was 22%. Median OS and PFS were significantly shorter with increasing IMDC, RMH and MDACC scores. The RMH and MDACC scores outperformed the IMDC score for predicting OS (RMH LR χ2=8.64; MDACC LR χ2=7.74; IMDC LR χ2=2.36) and PFS (RMH LR χ2=17.5; MDACC LR χ2=20.3; IMDC LR χ2=4.28). CONCLUSIONS: The RMH and MDACC prognostic scores can be used to predict OS for patients with mRCC in phase I trials and may guide patient selection. Patients with mRCC should be considered for phase I trials.

12.
J Immunother Cancer ; 8(2)2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33203661

RESUMO

BACKGROUND: To date, no systemic therapy, including immunotherapy, exists to improve clinical outcomes in metastatic uveal melanoma (UM) patients. To understand the role of immune infiltrates in the genesis, metastasis, and response to treatment for UM, we systematically characterized immune profiles of UM primary and metastatic tumors, as well as samples from UM patients treated with immunotherapies. METHODS: Relevant immune markers (CD3, CD8, FoxP3, CD68, PD-1, and PD-L1) were analyzed by immunohistochemistry on 27 primary and 31 metastatic tumors from 47 patients with UM. Immune gene expression profiling was conducted by NanoString analysis on pre-treatment and post-treatment tumors from patients (n=6) receiving immune checkpoint blockade or 4-1BB and OX40 dual costimulation. The immune signature of UM tumors responding to immunotherapy was further characterized by Ingenuity Pathways Analysis and validated in The Cancer Genome Atlas data set. RESULTS: Both primary and metastatic UM tumors showed detectable infiltrating lymphocytes. Compared with primary tumors, treatment-naïve metastatic UM showed significantly higher levels of CD3+, CD8+, FoxP3+ T cells, and CD68+ macrophages. Notably, levels of PD-1+ infiltrates and PD-L1+ tumor cells were low to absent in primary and metastatic UM tumors. No metastatic organ-specific differences were seen in immune infiltrates. Our NanoString analysis revealed significant differences in a set of immune markers between responders and non-responders. A group of genes relevant to the interferon-γ signature was differentially up-expressed in the pre-treatment tumors of responders. Among these genes, suppressor of cytokine signaling 1 was identified as a marker potentially contributing to the response to immunotherapy. A panel of genes that encoded pro-inflammatory cytokines and molecules were expressed significantly higher in pre-treatment tumors of non-responders compared with responders. CONCLUSION: Our study provides critical insight into immune profiles of UM primary and metastatic tumors, which suggests a baseline tumor immune signature predictive of response and resistance to immunotherapy in UM.

13.
Pharmaceuticals (Basel) ; 13(11)2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33182254

RESUMO

Lung cancers contribute to the greatest number of cancer-related deaths worldwide and still pose challenges in response to current treatment strategies. Non-small cell lung cancer (NSCLC) accounts for over 85% of lung cancers diagnosed in the United States and novel therapeutics are needed for the treatment of this disease. First and second generation targeted therapies against specific mutated or rearranged oncogenes in NSCLCs show anti-tumor activity and also increase survival. However, many NSCLC patients eventually develop resistance to these therapies or do not properly respond if they have central nervous system metastases. Thus, this review summarizes recent developments and findings related to the generation of novel targeted therapies recently or currently being developed to tackle hurdles that prior therapies were not able to overcome.

14.
ESMO Open ; 5(5)2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33097651

RESUMO

PURPOSE: The receptor tyrosine kinase rearranged during transfection (RET) can be oncogenically activated by gene fusions or point mutations. Multikinase inhibitors such as cabozantinib, lenvatinib and vandetanib have demonstrated activity in RET-dependent malignancies, and selective RET inhibitors (Selpercatinib and Pralsetinib) are in clinical trials. However, the responsiveness of RET-dependent malignancies to immune checkpoint inhibitors (ICIs) is unknown. We compared the time to treatment discontinuation (TTD) for ICI versus non-ICI therapy in patients with malignancies harbouring activating RET mutations or fusions (RET+). METHODS: A retrospective review of all RET+ patients who were referred to the phase I clinical trials programme at the University of Texas MD Anderson Cancer Center was conducted. TTD was estimated using Kaplan-Meier analysis. Multivariate analysis using the Cox proportional hazard model was performed to identify independent risk factors of treatment discontinuation. RESULTS: Of 70 patients who received systemic therapy for RET+ malignancies, 20 (28.6%) received ICI and 50 (71.4%) received non-ICI therapy. Non-ICI therapy was associated with decreased risk for treatment discontinuation compared with ICI in the overall population (HR=0.31; 95% CI 0.16-0.62; p=0.000834) and in patients with RET point mutations (HR=0.13; 95% CI 0.04-0.45; p=0.00134). In patients with RET fusions, non-ICI therapy was associated with a non-statistically significant decreased risk of treatment discontinuation (HR=0.59; 95% CI 0.25-1.4; p=0.24). ICI therapy and a diagnosis other than medullary thyroid cancer (MTC) were independent risk factors for treatment discontinuation. CONCLUSION: Our study supports the prioritisation of non-ICI over ICI therapy in patients with RET+ tumours.

15.
Artigo em Inglês | MEDLINE | ID: mdl-33123754

RESUMO

Although immunotherapy has achieved impressive durable clinical responses, many cancers respond only temporarily or not at all to immunotherapy. To find novel, targetable mechanisms of resistance to immunotherapy, patient-derived melanoma cell lines were transduced with 576 open reading frames, or exposed to arrayed libraries of 850 bioactive compounds, prior to co-culture with autologous tumor-infiltrating lymphocytes (TILs). The synergy between the targets and TILs to induce apoptosis, and the mechanisms of inhibiting resistance to TILs were interrogated. Gene expression analyses were performed on tumor samples from patients undergoing immunotherapy for metastatic melanoma. Finally, the effect of inhibiting the top targets on the efficacy of immunotherapy was investigated in multiple preclinical models. Aurora kinase was identified as a mediator of melanoma cell resistance to T-cell-mediated cytotoxicity in both complementary screens. Aurora kinase inhibitors were validated to synergize with T-cell-mediated cytotoxicity in vitro. The Aurora kinase inhibition-mediated sensitivity to T-cell cytotoxicity was shown to be partially driven by p21-mediated induction of cellular senescence. The expression levels of Aurora kinase and related proteins were inversely correlated with immune infiltration, response to immunotherapy and survival in melanoma patients. Aurora kinase inhibition showed variable responses in combination with immunotherapy in vivo, suggesting its activity is modified by other factors in the tumor microenvironment. These data suggest that Aurora kinase inhibition enhances T-cell cytotoxicity in vitro and can potentiate antitumor immunity in vivo in some but not all settings. Further studies are required to determine the mechanism of primary resistance to this therapeutic intervention.

16.
Nat Commun ; 11(1): 5332, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087697

RESUMO

Cytotoxic T lymphocyte (CTL)-based cancer immunotherapies have shown great promise for inducing clinical regressions by targeting tumor-associated antigens (TAA). To expand the TAA landscape of pancreatic ductal adenocarcinoma (PDAC), we performed tandem mass spectrometry analysis of HLA class I-bound peptides from 35 PDAC patient tumors. This identified a shared HLA-A*0101 restricted peptide derived from co-transcriptional activator Vestigial-like 1 (VGLL1) as a putative TAA demonstrating overexpression in multiple tumor types and low or absent expression in essential normal tissues. Here we show that VGLL1-specific CTLs expanded from the blood of a PDAC patient could recognize and kill in an antigen-specific manner a majority of HLA-A*0101 allogeneic tumor cell lines derived not only from PDAC, but also bladder, ovarian, gastric, lung, and basal-like breast cancers. Gene expression profiling reveals VGLL1 as a member of a unique group of cancer-placenta antigens (CPA) that may constitute immunotherapeutic targets for patients with multiple cancer types.


Assuntos
Antígenos de Neoplasias/imunologia , Neoplasias da Mama/imunologia , Proteínas de Ligação a DNA/imunologia , Neoplasias Pancreáticas/imunologia , Fatores de Transcrição/imunologia , Antígenos de Neoplasias/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Neoplasias da Mama/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/terapia , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Proteínas de Ligação a DNA/genética , Feminino , Perfilação da Expressão Gênica , Antígeno HLA-A1/imunologia , Humanos , Imunoterapia Adotiva , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Placenta/imunologia , Gravidez , Prognóstico , Linfócitos T Citotóxicos/imunologia , Fatores de Transcrição/genética
17.
Clin Cancer Res ; 26(22): 5830-5842, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32816889

RESUMO

PURPOSE: 90Y-FF-21101 is an Yttrium-90-conjugated, chimeric mAb that is highly specific for binding to human placental (P)-cadherin, a cell-to-cell adhesion molecule overexpressed and associated with cancer invasion and metastatic dissemination in many cancer types. We report the clinical activity of 90Y-FF-21101 in a first-in-human phase I study in patients with advanced solid tumors. PATIENTS AND METHODS: The safety and efficacy of 90Y-FF-21101 were evaluated in a phase I 3+3 dose-escalation study in patients with advanced solid tumors (n = 15) over a dose range of 5-25 mCi/m2. Dosimetry using 111In-FF-21101 was performed 1 week prior to assess radiation doses to critical organs. Patients who demonstrated clinical benefit received repeated 90Y-FF-21101 administration every 4 months. RESULTS: 111In-FF-21101 uptake was observed primarily in the spleen, kidneys, testes, lungs, and liver, with tumor uptake observed in the majority of patients. Organ dose estimates for all patients were below applicable limits. P-cadherin expression H-scores ranged from 0 to 242 with 40% of samples exhibiting scores ≥100. FF-21101 protein pharmacokinetics were linear with increasing antibody dose, and the mean half-life was 69.7 (±12.1) hours. Radioactivity clearance paralleled antibody clearance. A complete clinical response was observed in a patient with clear cell ovarian carcinoma, correlating with a high tumor P-cadherin expression. Stable disease was observed in a variety of other tumor types, without dose-limiting toxicity. CONCLUSIONS: The favorable safety profile and initial antitumor activity observed for 90Y-FF-21101 warrant further evaluation of this radioimmunotherapeutic (RIT) approach and provide initial clinical data supporting P-cadherin as a potential target for cancer treatment.

18.
Hepatology ; 2020 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-32779242

RESUMO

HSD17B13 (17-beta hydroxysteroid dehydrogenase 13) is genetically associated with human non-alcoholic fatty liver disease (NAFLD). Inactivating mutations in HSD17B13 protect humans from NAFLD- and alcohol-associated liver injury, fibrosis, cirrhosis and hepatocellular carcinoma, leading to clinical trials of anti-HSD17B13 therapeutic agents in humans. We aimed to study the in vivo function of HSD17B13 using a mouse model. Single-cell RNAseq and qPCR data revealed that hepatocytes are the main HSD17B13-expressing cells in mice and humans. We compared Hsd17b13 whole-body knockout (KO) mice and wild-type littermate controls (WT) fed regular chow (RC), high fat diet (HFD), Western diet (WD), or the NIAAA model of alcohol exposure. HFD and WD induced significant weight gain, hepatic steatosis and inflammation. However, there was no difference between genotypes with regards to body weight, liver weight, hepatic triglycerides (TG), histological inflammatory scores, expression of inflammatory- and fibrosis-related genes and hepatic retinoid levels. Compared to WT, KO mice on HFD had hepatic enrichment of most cholesterol esters, monoglycerides, and certain sphingolipids species. Extended feeding with WD for 10 months led to extensive liver injury, fibrosis and hepatocellular carcinoma, with no difference between genotypes. Under alcohol exposure, KO and WT mice showed similar hepatic TG and liver enzyme levels. Interestingly, chow-fed KO showed significantly higher body and liver weight compared to WT, while KO mice on obesogenic diets had a shift towards larger lipid droplets. In conclusion, extensive evaluation of Hsd17b13 deficiency in mice under several fatty liver-inducing dietary conditions didn't reproduce the protective role of HSD17B13 loss-of-function mutants in human NAFLD. Moreover, mouse Hsd17b13 deficiency induces weight gain under RC. It is crucial to understand inter-species differences prior to leveraging HSD17B13 therapies.

19.
Artigo em Inglês | MEDLINE | ID: mdl-32843426

RESUMO

Although BRAF inhibition has demonstrated activity in BRAF V600 -mutated brain tumors, ultimately these cancers grow resistant to BRAF inhibitor monotherapy. Parallel activation of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway has been implicated as a mechanism of primary and secondary resistance to BRAF inhibition. Moreover, it has been shown specifically that mTOR signaling activation occurs in BRAF-mutant brain tumors. We therefore conducted phase 1 trials combining vemurafenib with everolimus, enrolling five pediatric and young adults with BRAF V600 -mutated brain tumors. None of the patients required treatment discontinuation as a result of adverse events. Overall, two patients (40%) had a partial response and one (20%) had 12 mo of stable disease as best response. Co-targeting BRAF and mTOR in molecularly selected brain cancers should be further investigated.

20.
Cancers (Basel) ; 12(3)2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32197306

RESUMO

This article aims to summarize the current literature on genetic alterations related to tumors of the genitourinary tract. Novel associations have recently been reported between specific DNA alterations and genitourinary malignancies. The most common cause of chromosome 3p loss in clear cell renal cell carcinoma is a chromothripsis event, which concurrently generates a chromosome 5q gain. Specific patterns of clear cell renal cell carcinoma metastatic evolution have been uncovered. The first therapy targeting a specific molecular alteration has now been approved for urothelial carcinoma. Germline mutations in DNA damage repair genes and the transcription factor HOXB13 are associated with prostate cancer and may be targeted therapeutically. The genetic associations noted across different genitourinary cancers can inform potential screening approaches and guide novel targeted treatment strategies.

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