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  • American Association for Cancer Research (AACR)  (9)
  • 1
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    Online Resource
    Atypical KRASG12R Mutant Is Impaired in PI3K Signaling and Macropinocytosis in Pancreatic Cancer
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Discovery Vol. 10, No. 1 ( 2020-01-01), p. 104-123
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 10, No. 1 ( 2020-01-01), p. 104-123
    Abstract: Allele-specific signaling by different KRAS alleles remains poorly understood. The KRASG12R mutation displays uneven prevalence among cancers that harbor the highest occurrence of KRAS mutations: It is rare (∼1%) in lung and colorectal cancers, yet relatively common (∼20%) in pancreatic ductal adenocarcinoma (PDAC), suggesting context-specific properties. We evaluated whether KRASG12R is functionally distinct from the more common KRASG12D- or KRASG12V-mutant proteins (KRASG12D/V). We found that KRASG12D/V but not KRASG12R drives macropinocytosis and that MYC is essential for macropinocytosis in KRASG12D/V- but not KRASG12R-mutant PDAC. Surprisingly, we found that KRASG12R is defective for interaction with a key effector, p110α PI3K (PI3Kα), due to structural perturbations in switch II. Instead, upregulated KRAS-independent PI3Kγ activity was able to support macropinocytosis in KRASG12R-mutant PDAC. Finally, we determined that KRASG12R-mutant PDAC displayed a distinct drug sensitivity profile compared with KRASG12D-mutant PDAC but is still responsive to the combined inhibition of ERK and autophagy. Significance: We determined that KRASG12R is impaired in activating a key effector, p110α PI3K. As such, KRASG12R is impaired in driving macropinocytosis. However, overexpression of PI3Kγ in PDAC compensates for this deficiency, providing one basis for the prevalence of this otherwise rare KRAS mutant in pancreatic cancer but not other cancers. See related commentary by Falcomatà et al., p. 23. This article is highlighted in the In This Issue feature, p. 1
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-19-1006
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2607892-2
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  • 2
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    Combination Therapies with CDK4/6 Inhibitors to Treat KRAS- Mutant Pancreatic Cancer
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 1 ( 2023-01-04), p. 141-157
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 1 ( 2023-01-04), p. 141-157
    Abstract: Mutational loss of CDKN2A (encoding p16INK4A) tumor-suppressor function is a key genetic step that complements activation of KRAS in promoting the development and malignant growth of pancreatic ductal adenocarcinoma (PDAC). However, pharmacologic restoration of p16INK4A function with inhibitors of CDK4 and CDK6 (CDK4/6) has shown limited clinical efficacy in PDAC. Here, we found that concurrent treatment with both a CDK4/6 inhibitor (CDK4/6i) and an ERK–MAPK inhibitor (ERKi) synergistically suppresses the growth of PDAC cell lines and organoids by cooperatively blocking CDK4/6i-induced compensatory upregulation of ERK, PI3K, antiapoptotic signaling, and MYC expression. On the basis of these findings, a Phase I clinical trial was initiated to evaluate the ERKi ulixertinib in combination with the CDK4/6i palbociclib in patients with advanced PDAC (NCT03454035). As inhibition of other proteins might also counter CDK4/6i-mediated signaling changes to increase cellular CDK4/6i sensitivity, a CRISPR-Cas9 loss-of-function screen was conducted that revealed a spectrum of functionally diverse genes whose loss enhanced CDK4/6i growth inhibitory activity. These genes were enriched around diverse signaling nodes, including cell-cycle regulatory proteins centered on CDK2 activation, PI3K–AKT–mTOR signaling, SRC family kinases, HDAC proteins, autophagy-activating pathways, chromosome regulation and maintenance, and DNA damage and repair pathways. Novel therapeutic combinations were validated using siRNA and small-molecule inhibitor–based approaches. In addition, genes whose loss imparts a survival advantage were identified (e.g., RB1, PTEN, FBXW7), suggesting possible resistance mechanisms to CDK4/6 inhibition. In summary, this study has identified novel combinations with CDK4/6i that may have clinical benefit to patients with PDAC. Significance: CRISPR-Cas9 screening and protein activity mapping reveal combinations that increase potency of CDK4/6 inhibitors and overcome drug-induced compensations in pancreatic cancer.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-22-0391
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 3
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    Characterization of ABT-806, a Humanized Tumor-Specific Anti-EGFR Monoclonal Antibody
    American Association for Cancer Research (AACR) ; 2015
    In:  Molecular Cancer Therapeutics Vol. 14, No. 5 ( 2015-05-01), p. 1141-1151
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 14, No. 5 ( 2015-05-01), p. 1141-1151
    Abstract: Despite clinical efficacy, current approved agents targeting EGFR are associated with on-target toxicities as a consequence of disrupting normal EGFR function. MAb 806 is a novel EGFR antibody that selectively targets a tumor-selective epitope suggesting that a mAb 806-based therapeutic would retain antitumor activity without the on-target toxicities associated with EGFR inhibition. To enable clinical development, a humanized variant of mAb 806 designated ABT-806 was generated and is currently in phase 1 trials. We describe the characterization of binding and functional properties of ABT-806 compared with the clinically validated anti-EGFR antibody cetuximab. ABT-806 binds the mutant EGFRvIII with high affinity and, relative to cetuximab, exhibits increased potency against glioblastoma multiforme cell line and patient-derived xenografts expressing this form of the receptor. ABT-806 also inhibits the growth of squamous cell carcinoma xenograft models expressing high levels of wild-type EGFR, associated with inhibition of EGFR signaling, although higher doses of ABT-806 than cetuximab are required for similar activity. ABT-806 enhances in vivo potency of standard-of-care therapies used to treat glioblastoma multiforme and head and neck squamous cell carcinoma. An indium-labeled version of ABT-806, [111In]-ABT-806, used to investigate the relationship between dose and receptor occupancy, revealed greater receptor occupancy at lowers doses in an EGFRvIII-expressing model and significant uptake in an orthotopic model. Collectively, these results suggest that ABT-806 may have antitumor activity superior to cetuximab in EGFRvIII-expressing tumors, and similar activity to cetuximab in tumors highly overexpressing wild-type EGFR with reduced toxicity. Mol Cancer Ther; 14(5); 1141–51. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-14-0820
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 4
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    The Effect of HIV and HPV Coinfection on Cervical COX-2 Expression and Systemic Prostaglandin E2 Levels
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Prevention Research Vol. 5, No. 1 ( 2012-01-01), p. 34-40
    Details
    In: Cancer Prevention Research, American Association for Cancer Research (AACR), Vol. 5, No. 1 ( 2012-01-01), p. 34-40
    Abstract: Human immunodeficiency virus (HIV-1) infection causes chronic inflammation. COX-2–derived prostaglandin E2 (PGE2) has been linked to both inflammation and carcinogenesis. We hypothesized that HIV-1 could induce COX-2 in cervical tissue and increase systemic PGE2 levels and that these alterations could play a role in AIDS-related cervical cancer. Levels of cervical COX-2 mRNA and urinary PGE-M, a biomarker of systemic PGE2 levels, were determined in 17 HIV-negative women with a negative cervical human papilloma virus (HPV) test, 18 HIV-infected women with a negative HPV test, and 13 HIV-infected women with cervical HPV and high-grade squamous intraepithelial lesions on cytology. Cervical COX-2 levels were significantly associated with HIV and HPV status (P = 0.006 and 0.002, respectively). Median levels of urinary PGE-M were increased in HIV-infected compared with uninfected women (11.2 vs. 6.8 ng/mg creatinine, P = 0.02). Among HIV-infected women, urinary PGE-M levels were positively correlated with plasma HIV-1 RNA levels (P = 0.003). Finally, levels of cervical COX-2 correlated with urinary PGE-M levels (P = 0.005). This study shows that HIV-1 infection is associated with increased cervical COX-2 and elevated systemic PGE2 levels. Drugs that inhibit the synthesis of PGE2 may prove useful in reducing the risk of cervical cancer or systemic inflammation in HIV-infected women. Cancer Prev Res; 5(1); 34–40. ©2011 AACR.
    Type of Medium: Online Resource
    ISSN: 1940-6207 , 1940-6215
    URL: Article
    DOI: 10.1158/1940-6207.CAPR-11-0496
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
    detail.hit.zdb_id: 2422346-3
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  • 5
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    Abstract B15: CRISPR/Cas9 genetic screen identifies novel therapeutic strategies for treating HRAS mutant HNSCC with farnesyltransferase inhibitors (FTIs)
    American Association for Cancer Research (AACR) ; 2020
    In:  Clinical Cancer Research Vol. 26, No. 12_Supplement_2 ( 2020-06-15), p. B15-B15
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 26, No. 12_Supplement_2 ( 2020-06-15), p. B15-B15
    Abstract: Head and neck squamous cell carcinoma (HNSCC) affects more than 50,000 people annually. The five-year survival rate has not improved significantly in the last decades. In addition, many treatment modalities are associated with significant morbidity that negatively impacts survivors’ quality of life. Mutations in the HRAS oncogene are presented in 5-10% cases of HNSCC. Our group has established its critical importance for the growth and survival of HNSCC. HRAS protein undergoes crucial post-translational modifications prompted by the obligate addition of a farnesyl isoprenoid group, which is required for proper localization and insertion into the cell membrane, where it can engage effector molecules. FTIs block farnesylation and thus block HRAS activity. The FTI tipifarnib is under clinical evaluation for the treatment of HRAS mutant HNSCC, and preliminary findings showed some efficacy in this patient population. We sought strategies to enhance the efficacy of tipifarnib for the treatment of HRAS mutant HNSCC. We applied a novel CRISPR/Cas9 genetic screen to identify druggable targets that could be inhibited in combination with FTIs to improve treatment outcomes. We identified genes involved in regulating the ERK-MAPK and PI3K-AKT effector signaling pathways, autophagy regulation, chemokine signaling, and chromatin structure, that could potentially be targeted to increase tumor sensitivity to tipifarnib. Consistent with our genetic screening result of enhanced vulnerability to autophagy inhibition in tipifarnib-treated cells, we observed an increase in autophagic flux upon short-term treatment with tipifarnib alone, suggesting an attempt to compensate for nutrient stress. To overcome this effect, we tested the consequences of inhibiting autophagy pharmacologically in combination with tipifarnib. A panel of HRAS mutant HNSCC cell lines showed a synergistic increase in sensitivity to tipifarnib in combination with SBI-0206965 and MRT68921, two distinct preclinical inhibitors of the autophagy-promoting kinase ULK1. Clinical candidate ULK inhibitors are on the horizon. We suggest that the combination of tipifarnib with ULK inhibitors could be useful to sensitize HRAS mutant HNSCC to tipifarnib. Additional validation and mechanistic experiments are ongoing. Citation Format: Sehrish-Javaid, Craig M. Goodwin, Kirsten L. Bryant, Samuel D. George, Victoria V. Nguyen, Kathryn N. Lambert, Andrew M. Waters, Channing J. Der, Adrienne D. Cox. CRISPR/Cas9 genetic screen identifies novel therapeutic strategies for treating HRAS mutant HNSCC with farnesyltransferase inhibitors (FTIs) [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr B15.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1557-3265.AACRAHNS19-B15
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 6
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    A Phase I Study of ABT-751, an Orally Bioavailable Tubulin Inhibitor, Administered Daily for 21 Days Every 28 Days in Pediatric Patients with Solid Tumors
    American Association for Cancer Research (AACR) ; 2008
    In:  Clinical Cancer Research Vol. 14, No. 4 ( 2008-02-15), p. 1111-1115
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 14, No. 4 ( 2008-02-15), p. 1111-1115
    Abstract: Purpose: To determine the toxicity profile, dose-limiting toxicities (DLT), and maximum tolerated dose (MTD) of ABT-751 administered orally once daily for 21 days, repeated every 28 days in a pediatric population. Experimental Design: Patients who were ≤18 years with relapsed or refractory solid tumors and who were able to swallow capsules were eligible. The starting dose was 75 mg/m2/d (n = 3) and was escalated to 100 (n = 6), 130 (n = 5), and 165 (n = 3) mg/m2/d in cohorts of three to six patients. The MTD was determined from DLTs occurring during the first treatment cycle. Results: Nineteen children (median age, 13 years; range, 5-18 years) were enrolled, and 17 were evaluable for toxicity. Diagnoses included neuroblastoma (n = 9), sarcomas (n = 9), and other solid tumors (n = 1). DLTs included fatigue, sensory neuropathy, transient hypertension, neutropenia, thrombocytopenia, nausea, vomiting, dehydration, abdominal pain, and constipation. The MTD of ABT-751 administered daily for 21 days every 28 days was 100 mg/m2/d. Non-DLT at the MTD included bone marrow suppression, gastrointestinal toxicities (anorexia, abdominal pain, nausea, vomiting, and constipation), and sensory and motor neuropathies. The median number of cycles administered was one (range, one to five). Tolerance of repeated treatment cycles was poor. Conclusion: Fatigue, hematologic, and gastrointestinal toxicities limited the tolerability of ABT-751 administered to children on the once daily for 21 days every 28 days schedule. The MTD in children with solid tumors (100 mg/m2/d daily for 21 days) was similar to the recommended dose in adults with solid tumors (200 mg fixed dose) receiving the same dosing schedule.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-07-4097
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2008
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 7
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    A Phase 1 Study of ABT-751, an Orally Bioavailable Tubulin Inhibitor, Administered Daily for 7 Days Every 21 Days in Pediatric Patients with Solid Tumors
    American Association for Cancer Research (AACR) ; 2006
    In:  Clinical Cancer Research Vol. 12, No. 16 ( 2006-08-15), p. 4882-4887
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 12, No. 16 ( 2006-08-15), p. 4882-4887
    Abstract: Purpose: To determine the toxicity profile, dose-limiting toxicities, and maximum tolerated dose of ABT-751 administered orally once daily for 7 days, repeated every 21 days. Experimental Design: Patients who were ≤18 years of age, with relapsed or refractory solid tumors, and who were able to swallow capsules were eligible. The starting dose was 100 mg/m2/d (n = 3) and was escalated to 130 mg/m2/d (n = 6), 165 mg/m2/d (n = 6), 200 mg/m2/d (n = 6), and 250 mg/m2/d (n = 2) in cohorts of three to six patients. The maximum tolerated dose was determined from dose-limiting toxicities occurring during the first treatment cycle. Results: Twenty-four children (median age, 13 years; range, 4-18 years) were enrolled; 23 were evaluable for toxicity. Diagnoses included neuroblastoma (n = 8), sarcomas (n = 8), primary brain tumors (n = 2), Wilms' tumor (n = 2), and other solid tumors (n = 3). Dose-limiting toxicities (grade 3 sensory and motor neuropathy, grade 3 hypertension, and grade 3 fatigue) were observed in patients enrolled at the 250 mg/m2/d dose level. The maximum tolerated dose of ABT-751 administered daily for 7 days every 21 days was 200 mg/m2/d. Non-dose-limiting toxicities at the maximum tolerated dose included anemia, fatigue, peripheral sensory neuropathy, abdominal pain, nausea, constipation, anorexia, fever, and weight loss. Myelosuppression was minimal at the maximum tolerated dose. The median number of cycles administered is 2 (range, 1-50). No significant ABT-751-related cumulative toxicities were observed. Conclusion: ABT-751 is well tolerated in children. The recommended dose for phase 2 trials in solid tumors is 200 mg/m2/d administered orally, daily for 7 days every 21 days. This dose is & gt;40% higher than the maximum tolerated dose in adults receiving the same dosing schedule.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-06-0534
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2006
    detail.hit.zdb_id: 1225457-5
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  • 8
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    The Novel Polyamine Analogue CGC-11093 Enhances the Antimyeloma Activity of Bortezomib
    American Association for Cancer Research (AACR) ; 2008
    In:  Cancer Research Vol. 68, No. 12 ( 2008-06-15), p. 4783-4790
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 68, No. 12 ( 2008-06-15), p. 4783-4790
    Abstract: Multiple myeloma (MM) is an incurable plasma cell malignancy. The recent successes of the proteasome inhibitor bortezomib in MM therapy have prompted investigations of its efficacy in combination with other anticancer agents. Polyamines play important roles in regulating tumor cell proliferation and angiogenesis and represent an important therapeutic target. CGC-11093 is a novel polyamine analogue that has completed a phase I clinical trial for the treatment of cancer. Here, we report that CGC-11093 selectively augments the in vitro and in vivo antimyeloma activity of bortezomib. Specifically, the combination of CGC-11093 and bortezomib compromised MM viability and clonogenic survival, and increased drug-induced apoptosis over that achieved by either single agent. Xenografts of MM tumors treated with this combination had marked increases in phospho-c-Jun-NH2-kinase (JNK)-positive cells and apoptosis, and corresponding reductions in tumor burden, tumor vasculature, and the expression of proliferating cell nuclear antigen and the proangiogenic cytokine vascular endothelial growth factor. Furthermore, inhibition of JNK with a pharmacologic inhibitor or by selective knockdown blunted the efficacy of CGC-11093 and bortezomib. Therefore, CGC-11093 enhances the anticancer activity of bortezomib by augmenting JNK-mediated apoptosis and blocking angiogenesis. These findings support the study of the use of the combination of bortezomib and CGC-11093 in MM patients that fail to respond to frontline therapy. [Cancer Res 2008;68(12):4783–90]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-07-6483
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2008
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 9
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    Concurrent Inhibition of ERK and Farnesyltransferase Suppresses the Growth of HRAS Mutant Head and Neck Squamous Cell Carcinoma
    American Association for Cancer Research (AACR) ; 2022
    In:  Molecular Cancer Therapeutics Vol. 21, No. 5 ( 2022-05-04), p. 762-774
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 21, No. 5 ( 2022-05-04), p. 762-774
    Abstract: Human papilloma virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is a common cancer worldwide with an unmet need for more effective, less toxic treatments. Currently, both the disease and the treatment of HNSCC cause significant mortality and morbidity. Targeted therapies hold new promise for patients with HPV-negative status whose tumors harbor oncogenic HRAS mutations. Recent promising clinical results have renewed interest in the development of farnesyltransferase inhibitors (FTIs) as a therapeutic strategy for HRAS-mutant cancers. With the advent of clinical evaluation of the FTI tipifarnib for the treatment of HRAS-mutant HNSCC, we investigated the activity of tipifarnib and inhibitors of HRAS effector signaling in HRAS-mutant HNSCC cell lines. First, we validated that HRAS is a cancer driver in HRAS-mutant HNSCC lines. Second, we showed that treatment with the FTI tipifarnib largely phenocopied HRAS silencing, supporting HRAS as a key target of FTI antitumor activity. Third, we performed reverse-phase protein array analyses to profile FTI treatment-induced changes in global signaling, and conducted CRISPR/Cas9 genetic loss-of-function screens to identify previously unreported genes and pathways that modulate sensitivity to tipifarnib. Fourth, we determined that concurrent inhibition of HRAS effector signaling (ERK, PI3K, mTORC1) increased sensitivity to tipifarnib treatment, in part by overcoming tipifarnib-induced compensatory signaling. We also determined that ERK inhibition could block tipifarnib-induced epithelial-to-mesenchymal transition, providing a potential basis for the effectiveness of this combination. Our results support future investigations of these and other combination treatments for HRAS mutant HNSCC.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-21-0142
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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