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  • American Association for Cancer Research (AACR)  (22)
  • 1
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    Abstract 5785: EML4-ALK variant E6a/b;A20 positive NSCLC cell lines are associated with growth upon blocking MEK-ERK pathway
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 5785-5785
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 5785-5785
    Abstract: Background: The protein kinase B (PKB/AKT) and RAF/MEK/ERK signaling pathways are activated in a wide range of human cancer types. In many cases, concomitant inhibition of both pathways is necessary to block proliferation and induce cell death and tumor shrinkage. Several feedback mechanisms have been described in which inhibition of one pathway leads to activation of a parallel signaling pathway, thereby decreasing the effectiveness of targeted monotherapies. Materials and Methods: In order to determine which signalling core should be blocked for combinatorial treatment, we treated a panel of EML4-ALK positive lung cancer cell lines using MEK-ERK inhibitors. Resazurin assay was performed to evaluate cell viability. Protein levels were determined using western blotting. Results: In this study, we describe a feedback mechanism in which MEK-ERK inhibition leads to increased activation of AKT signaling in EML4-ALK variant (E6a/b;A20) positive NSCLC cell lines. Interestingly, EML4-ALK variant (E13;A20) NSCLC cell lines responds to MEK-ERK inhibitors and shows synergism when combined with ALK tyrosine kinase inhibitors. We found that feedback response in EML4-ALK variant (E6a/b;A20) positive NSCLC cells was mediated by the mammalian target of rapamycin complex 2-associated protein SIN1, resulting in increased survival and proliferation that depended on AKT signaling. Conclusions: Taken together, these results elucidate an important feedback network and contraindicate the use of MEK inhibitors as effective therapeutic strategy in EML4-ALK variant (E6a/b;A20) positive NSCLC. Citation Format: Bengt Hallberg, Ruth H. Palmer, Ganesh Umapathy, Dan E. Gustafsson, Joachim T. Siaw, Wasi Alam, Jikui Guan, Robert Doebele, Anh T. Le, Andrea Doak. EML4-ALK variant E6a/b;A20 positive NSCLC cell lines are associated with growth upon blocking MEK-ERK pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5785.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-5785
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 2
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    Metabolomic Profiling Reveals Potential Markers and Bioprocesses Altered in Bladder Cancer Progression
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 24 ( 2011-12-15), p. 7376-7386
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 24 ( 2011-12-15), p. 7376-7386
    Abstract: Although alterations in xenobiotic metabolism are considered causal in the development of bladder cancer, the precise mechanisms involved are poorly understood. In this study, we used high-throughput mass spectrometry to measure over 2,000 compounds in 58 clinical specimens, identifying 35 metabolites which exhibited significant changes in bladder cancer. This metabolic signature distinguished both normal and benign bladder from bladder cancer. Exploratory analyses of this metabolomic signature in urine showed promise in distinguishing bladder cancer from controls and also nonmuscle from muscle-invasive bladder cancer. Subsequent enrichment-based bioprocess mapping revealed alterations in phase I/II metabolism and suggested a possible role for DNA methylation in perturbing xenobiotic metabolism in bladder cancer. In particular, we validated tumor-associated hypermethylation in the cytochrome P450 1A1 (CYP1A1) and cytochrome P450 1B1 (CYP1B1) promoters of bladder cancer tissues by bisulfite sequence analysis and methylation-specific PCR and also by in vitro treatment of T-24 bladder cancer cell line with the DNA demethylating agent 5-aza-2′-deoxycytidine. Furthermore, we showed that expression of CYP1A1 and CYP1B1 was reduced significantly in an independent cohort of bladder cancer specimens compared with matched benign adjacent tissues. In summary, our findings identified candidate diagnostic and prognostic markers and highlighted mechanisms associated with the silencing of xenobiotic metabolism. The metabolomic signature we describe offers potential as a urinary biomarker for early detection and staging of bladder cancer, highlighting the utility of evaluating metabolomic profiles of cancer to gain insights into bioprocesses perturbed during tumor development and progression. Cancer Res; 71(24); 7376–86. ©2011 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-11-1154
    RVK:
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    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 3
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    Vimentin: A Novel Chemopreventive Target for Breast Cancer Metastasis.
    American Association for Cancer Research (AACR) ; 2009
    In:  Cancer Research Vol. 69, No. 24_Supplement ( 2009-12-15), p. 5063-5063
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 24_Supplement ( 2009-12-15), p. 5063-5063
    Abstract: Background: Cancer metastasis is the major cause of death in nearly all tumor types; however, most treatments target the primary tumor and not the highly invasive metastatic cells. We propose to prevent cancer metastasis by precisely targeting the cancer invasion machinery. To do this we disrupt a novel target-the vimentin cytoskeleton. Vimentin is overexpressed in nearly all invasive solid tumors and is critical for cell migration. Here we show that Withania sominifera root extracts (WRE) and one of its primary constituent, Withaferin A (WFA), targets vimentin to inhibit cancer cell motility and migration while having negligible effects on viability. WFA is a steroidal natural product with 4-rings (A-D) connected to a lactone ring. We test the hypothesis that WFA is an anti-invasive compound that disrupts vimentin function with limited toxicity.Material and Methods: We employ cutting-edge live cell confocal imaging studies in combination with traditional molecular biology techniques to dissect the precise mechanism of how WRE or WFA inhibits cancer cell migration and invasion. We have employed a wounding model and Matrigel invasion assay to determine the anti-migratory and anti-invasive properties of WRE and WFA using MDAMB-231 cells. We have used GFP-vimentin to visualize the changes in vimentin dynamics. Effect of WRE and WFA on cell cycle was analyzed by Flow cytometry.Results: Our results show WFA has weak anti-proliferative activity at low concentrations but potently inhibits breast cancer migration and invasion in a dose-dependent manner. High resolution confocal images reveal that in WFA-treated cells, vimentin fails to invade the lamellipodia resulting in decreased cell migration. This is supported by live cell confocal imaging showing that at high doses WFA treatment depolymerizes GFP: vimentin. Furthermore, treatment with WFA results in aberrant vimentin phosphorylation, likely resulting in a net depolymerized phenotype. In order to determine if the vimentin-binding A ring of WFA is critical for its anti-invasive efficacy, we synthesized and tested A-ring modified analogs of WFA. All three analogs showed severely reduced potency in inhibiting cancer cell migration and invasion, suggesting that the A ring is critical for its anti-invasive activity.Discussion: The present study shows that WRE or WFA inhibits breast cancer cell migration at nanomolar concentrations by disrupting vimentin at concentrations that have minimal effect on proliferation. We believe its strong anti-migratory activity make this an appropriate compound as an anti-metastatic chemopreventative. Ultimately, we envision WFA can be used as a vimentin-targeting chemopreventative in high-risk metastatic patients and has the potential to be used with traditional cytotoxics. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5063.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.SABCS-09-5063
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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    Abstract 3536: Targeting β-catenin with a Dicer-substrate siRNA (DsiRNA) in a sleeping beauty transposon-driven murine hepatoblastoma model
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 3536-3536
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 3536-3536
    Abstract: Hepatoblastoma (HB), the commonest pediatric liver tumor is frequently associated with an N-terminal deletion in the CTNNB1 gene, which encodes stable β-catenin and promotes nuclear localization and transactivation activity. In 80% of patients, nuclear localization of β-catenin and Yes Associated Protein (YAP), a Hippo-related transactivator, is seen together. Further, stable hepatic co-expression of Δ90-CTNNB1 and active-YAP in mice causes rapid and aggressive HB. Dicer-substrate siRNAs (DsiRNAs) are potent RNA interference (RNAi) triggers that that are efficacious in preclinical tumor models of diverse origin, and are currently under clinical evaluation. To determine if CTNNB1-targeting DsiRNAs have potential as a therapy in HB, we encapsulated this oligonucleotide payload into lipid nanoparticles (LNPs), and systemically administered into mice bearing CTNNB1/YAP-induced HB. The LNP platform used, termed EnCore (because of its specific Envelope and Core lipid components), enables high encapsulation efficiency, long-term stability, and consistent analytical criteria. Downstream of LNP-mediated DsiRNA delivery, both qPCR and in situ hybridization were used to visualize changes in CTNNB1 expression in both tumor and normal liver. Robust and specific silencing of CTNNB1 mRNA was achieved in the tumors. The distribution of mRNA knockdown within each tumor nodule suggests efficient extravasation and internalization of the LNP and its payload into the tumor parenchyma, in contrast to previous reports of vascular-channel limited nanoparticle accumulation in tumors. Intriguingly, a “liver-centric” LNP formulation, which delivers cargo efficiently to a normal liver due to rapid hepatic extraction and apolipoprotein-mediated internalization, was inactive in the tumors. Further evaluation demonstrated efficacy of β-catenin targeting in this model. In conclusion, we report a highly relevant modality of RNAi delivery in a mouse model of hepatoblastoma to target a classically-undruggable oncogene. Citation Format: Marc T. Abrams, Junyan Tao, Shanthi Ganesh, Wendy Cyr, Bo Ying, Martin Koser, Rokhand Arvan, Girish Chopda, Hank Dudek, Cheng Lai, Weimin Wang, Bob Brown, Satdarshan Monga. Targeting β-catenin with a Dicer-substrate siRNA (DsiRNA) in a sleeping beauty transposon-driven murine hepatoblastoma model. [abstract] . In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3536. doi:10.1158/1538-7445.AM2015-3536
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-3536
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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    Abstract CT025: Phase Ib study of adavosertib in combination with olaparib in patients with refractory solid tumors: Dose escalation
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. CT025-CT025
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. CT025-CT025
    Abstract: Background: Preclinical data suggest that adavosertib (AZD1775), a highly selective Wee1 inhibitor, enhances the antitumor effect of PARP inhibitors such as olaparib. The dose-escalation part of this Phase Ib study (NCT02511795) investigated the safety and tolerability of adavosertib plus olaparib in patients (pts) with refractory solid tumors to determine a maximum tolerated dose (MTD) and recommended Phase II dose (RP2D). Methods: Pts received adavosertib (QD or BID) for 3 consecutive days with 4 days off treatment (3/4), or 5 consecutive days with 2 days off (5/2), plus olaparib (BID) for 14 or 21 days of a 21-day cycle (Table). The MTD was the highest dose at which & lt;1/3 of evaluable pts had a dose-limiting toxicity (DLT). DLTs were hematologic grade (gr) ≥4 AEs lasting & gt;7 days, gr 3 thrombocytopenia with gr ≥2 bleeding, non-hematologic gr ≥3 AEs (excluding nausea, vomiting or diarrhea that responds to supportive care), liver function gr ≥3 AEs lasting & gt;48 hours or changes consistent with Hy’s Law, or any other toxicity that disrupted dosing for & gt;7 days. Results: 119 pts were treated (84 female; median age 59; most common primary tumor sites: ovary [21%], breast [16%] , lung [12.6%]) (Table). The most common gr ≥3 AEs were anemia (n=28, 23.5%), neutropenia (n=26, 21.8%), and thrombocytopenia (n=20, 16.8%) (all grouped terms). The most common DLTs were thrombocytopenia (n=4) and neutropenia (n=4); two pts experienced both. There were 4 SAEs with an outcome of death, 1 was treatment related. ORR for the total population, cohort 4.2 and cohort 7.4 was 11.1%, 30.8% and 0%, respectively. DCR was 55.7%, 76.9% and 53.8%, respectively. PK and biomarker data will be presented. Conclusions: Treatment with adavosertib plus olaparib showed antitumor activity, mostly at the MTD/RP2D for the BID schedule, which was determined to be adavosertib 175 mg (3/4) for 2/3 weeks plus olaparib 200 mg BID. The RP2D for QD schedule was adavosertib 200 mg (3/4) for 2/3 weeks plus olaparib 200 mg BID. Summary of study cohortsCohortAdavosertib doseOlaparib doseAdavosertib schedule, daysOlaparib schedule, daysPatients, n (evaluable,* n)Patients with a DLT, n (%)Grade ≥3 AEs,† n (%)ORR, n (%)DCR, n (%)1125 mg BID (3/4)100 mg BID1–3/8–101–143 (2)01 (33.3)03 (100)2150 mg BID (3/4)100 mg BID1–3/8–101–144 (4)02 (50)1 (25)2 (50)3.1175 mg BID (3/4)100 mg BID1–3/8–101–144 (2)03 (75)03 (75)3.2150 mg BID (3/4)200 mg BID1–3/8–101–147 (5)04 (57.1)1 (14.3)5 (71.4)4.1175 mg BID (3/4)200 mg BID1–3/8–101–147 (7)04 (57.1)1 (14.3)4 (57.1)4.2175 mg BID (3/4)200 mg BID1–3/8–101–2114 (11)1 (9.1)9 (64.3)4 (30.8)10 (76.9)4.3175 mg BID (3/4)200 mg BID1–3/8–10/15–171–2114 (11)2 (18.2)13 (92.9)1 (7.7)7 (50)5175 mg BID (3/4)300 mg BID1–3/8–101–145 (5)1 (20.0)3 (60.0)2 (50)4 (100)6.1250 mg QD (5/2)200 mg BID1–5/8–121–217 (4)2 (50.0)6 (85.7)1 (20)1 (16.7)6.2200 mg QD (5/2)200 mg BID1–5/8–121–217 (5)2 (40.0)4 (57.1)01 (14.3)7.1250 mg QD (3/4)200 mg BID1–3/8–101–2116 (14)2 (14.3)12 (75)010 (62.5)7.2250 mg QD (3/4)200 mg BID1–3/8–10/15–171–214 (4)1 (25.0)3 (75)1 (25)3 (75)7.3300 mg QD (3/4)200 mg BID1–3/8–101–213 (3)1 (33.3)2 (66.7)007.4200 mg QD (3/4)200 mg BID1–3/8–101–2113 (12)1 (8.3)3 (23.1)07 (53.8)8.1200 mg QD (3/4)300 mg BID1–3/8–101–2111 (9)1 (11.1)4 (36.4)04 (40)*Evaluable patients received & gt;75% of the planned dose of adavosertib and olaparib; †Common Terminology Criteria for Adverse Events. DCR, disease control rate; ORR, objective response rate Citation Format: Erika Hamilton, Gerald S. Falchook, Judy S. Wang, Siqing Fu, Amit Oza, So Karen, Esteban Rodrigo Imedio, Sanjeev Kumar, Lone Ottesen, Ganesh M. Mugundu, Juliann Chmielecki, Suzanne Jones, David R. Spigel, Bob T. Li. Phase Ib study of adavosertib in combination with olaparib in patients with refractory solid tumors: Dose escalation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT025.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-CT025
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    Phase II Single-arm Study of Durvalumab and Tremelimumab with Concurrent Radiotherapy in Patients with Mismatch Repair–proficient Metastatic Colorectal Cancer
    American Association for Cancer Research (AACR) ; 2021
    In:  Clinical Cancer Research Vol. 27, No. 8 ( 2021-04-15), p. 2200-2208
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 8 ( 2021-04-15), p. 2200-2208
    Abstract: Immune checkpoint inhibition (ICI) alone is not active in mismatch repair–proficient (MMR-P) metastatic colorectal cancer (mCRC), nor does radiotherapy alone result in objective systemic benefit. However, combined radiotherapy plus ICI can induce systemic antitumor immunity in preclinical and clinical models. Patients and Methods: In this single-center, phase II study, patients with chemotherapy-refractory MMR-P mCRC received durvalumab 1,500 mg plus tremelimumab 75 mg every 4 weeks plus radiotherapy. The primary endpoint was objective response rate (ORR) in nonirradiated lesions. Treatment and efficacy were correlated with peripheral immune cell profiles. Results: We enrolled 24 patients, and report outcomes after a median follow-up of 21.8 (range: 15.9–26.3) months. The ORR was 8.3% (2 patients) [95% confidence interval (CI), 1.0–27.0]. The median progression-free survival was 1.8 (95% CI, 1.7–1.9) months, median overall survival was 11.4 (95% CI, 10.1–17.4) months. Twenty five percent of patients (n = 6) had treatment-related grade 3–4 adverse events. We observed increased circulating CD8+ T lymphocyte activation, differentiation, and proliferation in patients with objective response. Conclusions: This combination of radiotherapy plus ICI study did not meet the prespecified endpoint criteria to be considered worthwhile for further study. However, rare instances of systemic immune augmentation and regression in nonirradiated lesions were observed (an abscopal response). Combination durvalumab and tremelimumab plus radiotherapy is feasible in MMR-P mCRC with a manageable safety profile. Further studies of novel immunotherapy combinations, and identification of biomarkers predictive of abscopal response are warranted.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-20-2474
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 7
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    Direct Pharmacological Inhibition of β-Catenin by RNA Interference in Tumors of Diverse Origin
    American Association for Cancer Research (AACR) ; 2016
    In:  Molecular Cancer Therapeutics Vol. 15, No. 9 ( 2016-09-01), p. 2143-2154
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 15, No. 9 ( 2016-09-01), p. 2143-2154
    Abstract: The Wnt/β-catenin pathway is among the most frequently altered signaling networks in human cancers. Despite decades of preclinical and clinical research, efficient therapeutic targeting of Wnt/β-catenin has been elusive. RNA interference (RNAi) technology silences genes at the mRNA level and therefore can be applied to previously undruggable targets. Lipid nanoparticles (LNP) represent an elegant solution for the delivery of RNAi-triggering oligonucleotides to disease-relevant tissues, but have been mostly restricted to applications in the liver. In this study, we systematically tuned the composition of a prototype LNP to enable tumor-selective delivery of a Dicer-substrate siRNA (DsiRNA) targeting CTNNB1, the gene encoding β-catenin. This formulation, termed EnCore-R, demonstrated pharmacodynamic activity in subcutaneous human tumor xenografts, orthotopic patient-derived xenograft (PDX) tumors, disseminated hematopoietic tumors, genetically induced primary liver tumors, metastatic colorectal tumors, and murine metastatic melanoma. DsiRNA delivery was homogeneous in tumor sections, selective over normal liver and independent of apolipoprotein-E binding. Significant tumor growth inhibition was achieved in Wnt-dependent colorectal and hepatocellular carcinoma models, but not in Wnt-independent tumors. Finally, no evidence of accelerated blood clearance or sustained liver transaminase elevation was observed after repeated dosing in nonhuman primates. These data support further investigation to gain mechanistic insight, optimize dose regimens, and identify efficacious combinations with standard-of-care therapeutics. Mol Cancer Ther; 15(9); 2143–54. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-16-0309
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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    Abstract P6-10-14: Lysosomal acid lipase (LIPA) as a novel therapeutic vulnerability for treating TNBC
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 5_Supplement ( 2023-03-01), p. P6-10-14-P6-10-14
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. P6-10-14-P6-10-14
    Abstract: Background: TNBCs have the highest mortality rate among all BC subtypes. There is thus an urgent and unmet need for effective targeted therapies in TNBC. Recently we, identified a novel agent ERX-41 that showed good efficacy in treating TNBC in preclinical mouse models, however, its molecular action remain unknown. In this study, we identified LIPA as novel molecular target of ERX-41. Methods: We have used CRISPR knockout pooled library and multiple TNBC models for identifying molecular target of ERX-41. Mechanistic studies were performed using LIPA mutants, RNA-seq, Turbo-ID mapping, Mass spectrometry, Immunoprecipitation, and Western blotting. The in vivo efficacy of ERX-41 was examined using four different patient-derived xenograft (PDX) models. We evaluated LIPA protein expression in TNBC using tissue microarray (TMA). Results: To identify the molecular target of ERX-41, we performed an unbiased CRISPR–Cas9 knockout (KO) screen in MDA-MB-231 cells and the results identified LIPA as a top hit. KO of LIPA alone (which encodes lysosomal acid lipase (LAL) abrogated cytotoxic response to ERX-41. Cellular thermal shift assays confirmed that ERX-41 binds to LAL. In silico modelling and mutational studies confirmed that ERX-41 interacts with LAL through residues in its LXXLL domain and that ERX-41 ability to induce ER stress and cell death in TNBC is independent of the lipase activity of LAL. Unbiased RNA-seq studies with and without ERX-41 in parental and LIPA KO SUM-159 cells revealed induction of genes involved in ER stress and UPR response by ERX-41 in parental SUM-159 cells but not in cells with LIPA KO. Ultrastructural studies using live-cell confocal microscopy show that LIPA KO abrogated ER morphological changes at 2 and 4 h after ERX-41 treatment. Further, subcellular localization studies showed LIPA localizes to endoplasmic reticulum (ER). Unbiased proteomic approaches (TurboID and DIA mass spec) identified a core set of proteins that were both LAL binders and affected by ERX-41 treatment. GO analyses of LAL binding proteins confirmed their involvement in protein folding. Tumor micro array (TMA) analyses confirmed that & gt;80% of primary TNBC tumors had significant and detectable LAL protein expression in contrast, normal breast tissue had lower LAL expression. ERX-41 (10 mg/kg body weight) decreased growth of four distinct TNBC patient-derived xenografts (PDXs) in vivo. Conclusions: Our results identified a new molecular target (LAL) for ERX-41 and novel mechanism of action (disruption of protein folding and induction of ER stress) that may have utility in treating patients with TNBC. Citation Format: Suryavathi Viswanadhapalli, Xihui Liu, Uday Pratap, Gangadhara R. Sareddy, Susan T. Weintraub, Ganesh V. Raj, Jung-Mo Ahn, Ratna K. Vadlamudi. Lysosomal acid lipase (LIPA) as a novel therapeutic vulnerability for treating TNBC [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-10-14.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS22-P6-10-14
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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    Abstract 3533: Systemic delivery of CTNNB1 Dicer-substrate siRNAs (DsiRNAs) leads to efficient oncogene silencing in diverse tumor types of extra hepatic origin
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 3533-3533
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 3533-3533
    Abstract: The β-catenin/Wnt pathway is consistently activated in human tumors, including & gt;50% of hepatocellular carcinomas (HCC) and & gt;80% of colorectal cancers (CRC). This is often caused directly by tumorigenic mutations in the CTNNB1 gene, which encodes β-catenin protein. Preclinical evidence in genetic cancer models strongly suggests that inhibiting β-catenin function would yield therapeutic benefit to many cancer patients. Since β-catenin is very challenging to target via conventional modalities, no efficacious therapy targeting β-catenin has emerged despite decades of research. RNA interference (RNAi) technology has enabled the inhibition of previously undruggable targets at the mRNA level and has advanced to late-stage clinical development for several indications. However, the clinical application of RNAi has proven to be most successful for targeting mRNAs in the normal liver, and challenges remain with developing formulations that efficiently deliver to extra-hepatic tumors. Here we describe the development and characterization of a platform to treat tumors of diverse primary tissue origin and metastatic location with CTNNB1-targeting DsiRNA. Tumor types tested included xenograft tumors of colorectal origin (CRC), experimental melanoma lung metastases, and difficult-to-transfect leukemia cells which have infiltrated the spleen. In addition to strong silencing of CTNNB1 mRNA, & gt;75% inhibition of tumor growth was observed for a CRC xenograft model. This was achieved by formulating the DisRNA payload in a lipid nanoparticle (LNP) platform termed EnCore (because of its specific Envelope and Core lipid components). EnCore activity against multiple tumors was further improved by optimizing critical cationic lipid and PEG-lipid components. Importantly, studies in knockout mice demonstrate that in vivo tumor activity is independent of Apolipoprotein E, which has been widely described as an essential endogenous ligand for internalization of LNPs into hepatocytes. This strongly suggests that Encore-mediated delivery to tumors in vivo is independent of the ApoE/LDLR system. DCR-MYC, an EnCore-delivered DsiRNA targeting MYC mRNA, is currently in Phase I clinical trials. Further evaluation of LNP-delivered DsiRNAs in PK/PD and efficacy models, including PDX and GEMM will guide a clinical development strategy for CTNNB1 DsiRNA. Citation Format: Shanthi Ganesh, Bo Ying, Martin Koser, Wendy Cyr, Girish Chopda, Hank Dudek, Cheng Lai, Weimin Wang, Bob Brown, Marc T. Abrams. Systemic delivery of CTNNB1 Dicer-substrate siRNAs (DsiRNAs) leads to efficient oncogene silencing in diverse tumor types of extra hepatic origin. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3533. doi:10.1158/1538-7445.AM2015-3533
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-3533
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 10
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    SMAD4 Loss in Colorectal Cancer Patients Correlates with Recurrence, Loss of Immune Infiltrate, and Chemoresistance
    American Association for Cancer Research (AACR) ; 2019
    In:  Clinical Cancer Research Vol. 25, No. 6 ( 2019-03-15), p. 1948-1956
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 6 ( 2019-03-15), p. 1948-1956
    Abstract: SMAD4 has shown promise in identifying patients with colorectal cancer at high risk of recurrence or death. Experimental Design: A discovery cohort and independent validation cohort were classified by SMAD4 status. SMAD4 status and immune infiltrate measurements were tested for association with recurrence-free survival (RFS). Patient-derived xenografts from SMAD4-deficient and SMAD4-retained tumors were used to examine chemoresistance. Results: The discovery cohort consisted of 364 patients with stage I–IV colorectal cancer. Median age at diagnosis was 53 years. The cohort consisted of 61% left-sided tumors and 62% stage II/III patients. Median follow-up was 5.4 years (interquartile range, 2.3–8.2). SMAD4 loss, noted in 13% of tumors, was associated with higher tumor and nodal stage, adjuvant therapy use, fewer tumor-infiltrating lymphocytes (TIL), and lower peritumoral lymphocyte aggregate (PLA) scores (all P & lt; 0.04). SMAD4 loss was associated with worse RFS (P = 0.02). When stratified by SMAD4 and immune infiltrate status, patients with SMAD4 loss and low TIL or PLA had worse RFS (P = 0.002 and P = 0.006, respectively). Among patients receiving 5-fluorouracil (5-FU)-based systemic chemotherapy, those with SMAD4 loss had a median RFS of 3.8 years compared with 13 years for patients with SMAD4 retained. In xenografted mice, the SMAD4-lost tumors displayed resistance to 5-FU. An independent cohort replicated our findings, in particular, the association of SMAD4 loss with decreased immune infiltrate, as well as worse disease-specific survival. Conclusions: Our data show SMAD4 loss correlates with worse clinical outcome, resistance to chemotherapy, and decreased immune infiltrate, supporting its use as a prognostic marker in patients with colorectal cancer.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-18-1726
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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