Publications by authors named "John H Yim"

54 Publications

Phase II Trial of Neoadjuvant Carboplatin and Nab-Paclitaxel in Patients with Triple-Negative Breast Cancer.

Oncologist 2021 Mar 8;26(3):e382-e393. Epub 2020 Nov 8.

Department of Medical Oncology and Therapeutic Research, City of Hope Comprehensive Cancer Center, Duarte, California, USA.

Background: In this phase II clinical trial, we evaluated the efficacy of the nonanthracycline combination of carboplatin and nab-paclitaxel in early stage triple-negative breast cancer (TNBC).

Patients And Methods: Patients with newly diagnosed stage II-III TNBC (n = 69) were treated with neoadjuvant carboplatin (area under the curve 6) every 28 days for four cycles plus nab-paclitaxel (100 mg/m ) weekly for 16 weeks. Pathological complete response (pCR) and residual cancer burden (RCB) were analyzed with germline mutation status, tumor-infiltrating lymphocytes (TILs), TNBC molecular subtype, and GeparSixto immune signature (GSIS).

Results: Sixty-seven patients were evaluable for safety and response. Fifty-three (79%) patients experienced grade 3/4 adverse events, including grade 3 anemia (43%), neutropenia (39%), leukopenia (15%), thrombocytopenia (12%), fatigue (7%), peripheral neuropathy (7%), neutropenia (16%), and leukopenia (1%). Twenty-four patients (35%) had at least one dose delay, and 50 patients (72%) required dose reduction. Sixty-three (94%) patients completed scheduled treatment. The responses were as follows: 32 of 67 patients (48%) had pCR (RCB 0), 10 of 67 (15%) had RCB I, 19 of 67 (28%) had RCB II, 5 of 67 (7%) had RCB III, and 1 of 67 (2%) progressed and had no surgery. Univariate analysis showed that immune-hot GSIS and DNA repair defect (DRD) were associated with higher pCR with odds ratios of 4.62 (p = .005) and 4.76 (p = .03), respectively, and with RCB 0/I versus RCB II/III with odds ratio 4.80 (p = .01). Immune-hot GSIS was highly correlated with DRD status (p = .03), TIL level (p < .001), and TNBC molecular subtype (p < .001). After adjusting for age, race, stage, and grade, GSIS remained associated with higher pCR and RCB class 0/I versus II/III with odds ratios 7.19 (95% confidence interval [CI], 2.01-25.68; p = .002) and 8.95 (95% CI, 2.09-38.23; p = .003), respectively.

Conclusion: The combination of carboplatin and nab-paclitaxel for early stage high-risk TNBC showed manageable toxicity and encouraging antitumor activity. Immune-hot GSIS is associated with higher pCR rate and RCB class 0/1. This study provides an additional rationale for using nonanthracycline platinum-based therapy for future neoadjuvant trials in early stage TNBCs. Clinical trial identification number: NCT01525966 IMPLICATIONS FOR PRACTICE: Platinum is an important neoadjuvant chemotherapy agent for treatment of early stage triple-negative breast cancer (TNBC). In this study, carboplatin and nab-paclitaxel were well tolerated and highly effective in TNBC, resulting in pathological complete response of 48%. In univariate and multivariate analyses adjusting for age, race, tumor stage and grade, "immune-hot" GeparSixto immune signature (GSIS) and DNA repair defect (DRD) were associated with higher pathological complete response (pCR) and residual cancer burden class 0/1. The association of immune-hot GSIS with higher pCR holds promise for de-escalating neoadjuvant chemotherapy for patients with early stage TNBC. Although GSIS is not routinely used in clinic, further development of this immune signature into a clinically applicable assay is indicated.
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http://dx.doi.org/10.1002/onco.13574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930424PMC
March 2021

Inhibition of Autophagy Amplifies Baicalein-Induced Apoptosis in Human Colorectal Cancer.

Mol Ther Oncolytics 2020 Dec 29;19:1-7. Epub 2020 Aug 29.

Department of Surgery, City of Hope Medical Center, Duarte, CA, USA.

Baicalein is a Chinese herbal compound extracted from that has anti-tumor properties. The aim of this study was to elucidate the mechanisms of action of baicalein against human colorectal cancer cell lines and to assess whether the anti-proliferative effects of baicalein may be amplified with autophagy inhibition. Human colon cancer cell lines (HT-29, HCT-116, SW480, and SW620) were treated with baicalein alone and in combination with the autophagy inhibitor chloroquine (CQ). Baicalein reduced cell viability in all four colon cancer lines in a dose-dependent fashion. Combination treatment of baicalein and the autophagy inhibitor CQ significantly decreased cell viability compared with baicalein alone in HT-29 and HCT-116 cell lines. Western blot analysis of the HCT-116 cell line treated with both baicalein and CQ demonstrated increased expression of LC3-II, a component of autophagy. The combination of baicalein with CQ culminated in activation of caspase-3-mediated apoptosis. These findings demonstrate that inhibition of autophagy enhanced apoptotic cell death induced by baicalein treatment in colon cancer cell lines. Future work will assess other targetable apoptotic pathways activated by baicalein and autophagy inhibition.
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http://dx.doi.org/10.1016/j.omto.2020.08.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522588PMC
December 2020

Synergistic Anti-Tumor Activity by Targeting Multiple Signaling Pathways in Ovarian Cancer.

Cancers (Basel) 2020 Sep 10;12(9). Epub 2020 Sep 10.

Department of Surgery, City of Hope National Med Center, Duarte, CA 91010, USA.

More effective therapy is needed to improve the survival of patients with advanced and recurrent ovarian cancer. Preclinical and early clinical studies with single molecular targeted agents have shown limited antitumor activity in ovarian cancer, likely due to compensation by alternative growth/survival pathways. An emerging strategy in overcoming resistance is to combine inhibitors targeting multiple pathways. In this study, we used a novel strategy of combining several FDA-approved targeted drugs, including sunitinib, dasatinib, and everolimus, in human ovarian cancers. Combination of the tyrosine kinase inhibitor sunitinib with the SRC inhibitor dasatinib showed synergistic anti-tumor activity in human ovarian cancer cells. The increased activity was associated with inhibition of the STAT3, SRC, and MAPK signaling pathways, but not AKT signaling. To inhibit the PI3K/AKT/mTOR pathway, we added the mTOR inhibitor everolimus, which further increased anti-tumor activity in cells. Combined treatment with sunitinib, dasatinib, and everolimus also resulted in greater inhibition of human ovarian tumor growth in mice. Furthermore, the triple combination also synergistically increased the anti-tumor activity of paclitaxel, both in vitro and in vivo. Taken together, our results demonstrate that simultaneous inhibition of several signaling pathways results in better anti-tumor activity compared to inhibiting any of these signaling pathways alone.
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http://dx.doi.org/10.3390/cancers12092586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564386PMC
September 2020

Breast cancer induces systemic immune changes on cytokine signaling in peripheral blood monocytes and lymphocytes.

EBioMedicine 2020 Feb 22;52:102631. Epub 2020 Jan 22.

Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010, USA. Electronic address:

Background: It is increasingly recognized that cancer progression induces systemic immune changes in the host. Alterations in number and function of immune cells have been identified in cancer patients' peripheral blood and lymphoid organs. Recently, we found dysregulated cytokine signaling in peripheral blood T cells from breast cancer (BC) patients, even those with localized disease.

Methods: We used phosphoflow cytometry to determine the clinical significance of cytokine signaling responsiveness in peripheral blood monocytes from non-metastatic BC patients at diagnosis. We also examined the correlation between cytokine signaling in peripheral monocytes and the number of tumor-infiltrating macrophages in paired breast tumors.

Findings: Our results show that cytokine (IFNγ) signaling may also be dysregulated in peripheral blood monocytes at diagnosis, specifically in BC patients who later relapsed. Some patients exhibited concurrent cytokine signaling defects in monocytes and lymphocytes at diagnosis, which predict the risk of future relapse in two independent cohorts of BC patients. Moreover, IFNγ signaling negatively correlates with expression of CSF1R on monocytes, thus modulating their ability to infiltrate into tumors.

Interpretation: Our results demonstrate that tumor-induced systemic immune changes are evident in peripheral blood immune cells for both myeloid and lymphoid lineages, and point to cytokine signaling responsiveness as important biomarkers to evaluate the overall immune status of BC patients.

Funding: This study was supported by the Department of Defense Breast Cancer Research Program (BCRP), The V Foundation, Stand Up to Cancer (SU2C), and Breast Cancer Research Foundation (BCRF).
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http://dx.doi.org/10.1016/j.ebiom.2020.102631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992943PMC
February 2020

Insurance Status Predicts Survival in Women with Breast Cancer: Results of Breast and Cervical Cancer Treatment Program in California.

Ann Surg Oncol 2020 Jul 21;27(7):2177-2187. Epub 2020 Jan 21.

Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA.

Background And Purpose: The Breast and Cervical Cancer Treatment Program (BCCTP) Act, passed by Congress in 2000, provides time-limited coverage to uninsured breast or cervical cancer patients. We examine survival differences between BCCTP cases and insured controls.

Methods: Stage I-III breast cancer patients, covered under California's BCCTP from 2005 to 2009 (N = 6343), were 1:1 matched with California Cancer Registry controls on age, race/ethnicity, and cancer stage. Overall and disease-specific (OS and DSS) survival were compared using multivariate regression.

Results: BCCTP cases were more often unmarried [odds ratio (OR) 2.47, 95% confidence interval (CI) 2.30-2.66], with poorly/undifferentiated tumors (OR 1.26, CI 1.13-1.40), classified as ER negative (OR 1.10, CI 1.02-1.20) and/or PR negative (OR 1.09, CI 1.01-1.17). Cases were more likely to undergo mastectomy (OR 1.13, CI 1.05-1.21) or no surgery (OR 1.64, CI 1.31-2.05) versus lumpectomy. Cases were also more likely to undergo radiation (OR 1.11, CI 1.03-1.19). Endocrine therapy rates were marginally lower in cases (OR 0.93, CI 0.86-1.00). OS and DSS were shorter in BCCTP cases on multivariate analysis (HR 1.29, CI 1.17-1.42 and HR 1.27, CI 1.14-1.42, respectively). When stratified by socioeconomic status (SES), cases had significantly shorter OS and DSS except in the lowest quintile. When stratified by stage, cases had significantly shorter OS and DSS, except for stage I.

Conclusions: The BCCTP provides uninsured breast cancer patients with comprehensive and timely care. Although our results suggest that BCCTP delivers quality care, BCCTP patients have shorter survival rates, even after accounting for SES and stage differences. Further assistance to vulnerable populations is warranted, including longer duration of treatment coverage, and surveillance adhering to NCCN compliant surveillance programs.
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http://dx.doi.org/10.1245/s10434-019-08116-xDOI Listing
July 2020

Phase I clinical trial of the combination of eribulin and everolimus in patients with metastatic triple-negative breast cancer.

Breast Cancer Res 2019 11 8;21(1):119. Epub 2019 Nov 8.

Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center and Beckman Research Institute, 1500 E. Duarte Road, Duarte, CA, 91010, USA.

Background: Alteration of the PI3K/AKT/mTOR pathway is a common genomic abnormality detected in triple-negative breast cancer (TNBC). Everolimus acts synergistically with eribulin in TNBC cell lines and xenograft models. This phase I trial was designed to test the safety and tolerability of combining eribulin and everolimus in patients with metastatic TNBC.

Methods: The primary objective of this study was to evaluate the safety and toxicities of the combination. Patients with metastatic TNBC who had up to four lines of prior chemotherapies were enrolled. The combination of eribulin and everolimus was tested using three dosing levels: A1 (everolimus 5 mg daily; eribulin 1.4 mg/m days 1 and 8 every 3 weeks), A2 (everolimus 7.5 mg daily; eribulin 1.4 mg/m, days 1 and 8 every 3 weeks), and B1 (everolimus 5 mg daily; eribulin 1.1 mg/m days 1 and 8 every 3 weeks).

Results: Twenty-seven patients with median age 55 years were enrolled. Among 8 evaluable patients who received dose level A1, 4 had dose-limiting toxicities (DLTs). Among 3 evaluable patients treated with dose level A2, 2 had DLTs. Among 12 evaluable patients who received dose level B1, 4 had DLTs. The DLTs were neutropenia, stomatitis, and hyperglycemia. Over the study period, 59% had a ≥ grade 3 toxicity, 44% had ≥ grade 3 hematologic toxicities, and 22% had grade 4 hematologic toxicities. The most common hematological toxicities were neutropenia, leukopenia, and lymphopenia. Thirty-three percent had grade 3 non-hematologic toxicities. The most common non-hematological toxicities were stomatitis, hyperglycemia, and fatigue. The median number of cycles completed was 4 (range 0-8). Among 25 eligible patients, 9 patients (36%) achieved the best response as partial response, 9 (36%) had stable disease, and 7 (28%) had progression. The median time to progression was 2.6 months (95% CI [2.1, 4.0]), and median overall survival (OS) was 8.3 months (95% CI [5.5, undefined]).

Conclusion: Eribulin 1.1 mg/m days 1 and 8 every 3 weeks with everolimus 5 mg daily was defined as the highest dose with acceptable toxicity (RP2D). The combination is safe, and efficacy is modest. A post hoc analysis showed that participants that used dexamethasone mouthwash stayed on treatment for one additional cycle.

Trial Registration: ClinicalTrials.gov, NCT02120469. Registered 18 April 2014.
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http://dx.doi.org/10.1186/s13058-019-1202-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839083PMC
November 2019

Eribulin Synergistically Increases Anti-Tumor Activity of an mTOR Inhibitor by Inhibiting pAKT/pS6K/pS6 in Triple Negative Breast Cancer.

Cells 2019 08 30;8(9). Epub 2019 Aug 30.

Division of Surgery, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Rd., Duarte, CA 91010, USA.

Unlike other breast cancer subtypes, patients with triple negative breast cancer (TNBC) have poor outcomes and no effective targeted therapies, leaving an unmet need for therapeutic targets. Efforts to profile these tumors have revealed the PI3K/AKT/mTOR pathway as a potential target. Activation of this pathway also contributes to resistance to anti-cancer agents, including microtubule-targeting agents. Eribulin is one such microtubule-targeting agent that is beneficial in treating taxane and anthracycline refractory breast cancer. In this study, we compared the effect of eribulin on the PI3K/AKT/mTOR pathway with other microtubule-targeting agents in TNBC. We found that the phosphorylation of AKT was suppressed by eribulin, a microtubule depolymerizing agent, but activated by paclitaxel, a microtubule stabilizing agent. The combination of eribulin and everolimus, an mTOR inhibitor, resulted in an increased reduction of p-S6K1 and p-S6, a synergistic inhibition of cell survival in vitro, and an enhanced suppression of tumor growth in two orthotopic mouse models. These findings provide a preclinical foundation for targeting both the microtubule cytoskeleton and the PI3K/AKT/mTOR pathway in the treatment of refractory TNBC.
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http://dx.doi.org/10.3390/cells8091010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770784PMC
August 2019

Resident memory CD8+ T cells within cancer islands mediate survival in breast cancer patients.

JCI Insight 2019 10 3;4(19). Epub 2019 Oct 3.

Department of Immuno-Oncology.

CD8+ tumor-infiltrating lymphocytes (TILs) correlate with relapse-free survival (RFS) in most cancer types, including breast cancer. However, subset composition, functional status, and spatial location of CD8+ TILs in relation to RFS in human breast tumors remain unclear. Spatial tissue analysis via quantitative immunofluorescence showed that infiltration of CD8+ T cells into cancer islands was more significantly associated with RFS than CD8+ T cell infiltration into either tumor stroma or total tumor. Localization into cancer islands within tumors is mediated by expression of the integrin CD103, which is a marker for tissue-resident memory T cells (TRMs). Analysis of fresh tumor samples revealed that CD8+ TRMs are functionally similar to other CD8+ TILs, suggesting that the basis of their protective effect is their spatial distribution rather than functional differences. Indeed, CD103+ TRMs, as compared with CD103-CD8+ TILs, are enriched within cancer islands, and CD8+ TRM proximity to cancer cells drives the association of CD8+ TIL densities with RFS. Together, these findings reveal the importance of cancer island-localized CD8+ TRMs in surveillance of the breast tumor microenvironment and as a critical determinant of RFS in patients with breast cancer.
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http://dx.doi.org/10.1172/jci.insight.130000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795408PMC
October 2019

Increasing Antitumor Activity of JAK Inhibitor by Simultaneous Blocking Multiple Survival Signaling Pathways in Human Ovarian Cancer.

Transl Oncol 2019 Aug 26;12(8):1015-1025. Epub 2019 May 26.

Department of Surgery, Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 East Duarte Rd., Duarte, CA 91010. Electronic address:

Many signaling pathways, including the JAK/STAT3 pathway, are aberrantly activated and associated with ovarian cancer growth and progression. However, inhibition of STAT3 pathway alone was not sufficient to effectively block human ovarian cancer cell survival in vitro, which could be due to the activation and compensation of multiple survival pathways. In this study, we investigated a strategy that can enhance antitumor activity of JAK/STAT3 inhibitor by combining with inhibitors targeting other growth and survival pathways. We found that the in vitro activity of JAKi was remarkably increased when additional survival pathway was blocked. Blocking SRC pathway with SRC inhibitor (SRCi) increased the efficacy of JAKi more effectively than blocking AKT or MAPK pathway. The increased activity of JAKi in combination with SRCi is synergistic and associated with attenuation of p-STAT3, p-SRC, p-AKT and p-MAPK and increased inhibition of p-AKT. Simultaneous blockade of multiple survival pathways by combining JAKi with both AKT inhibitor (AKTi) and MEK inhibitor (MEKi) also resulted in a synergistic inhibition of cell survival. Furthermore, the combined treatment of JAKi and SRCi led to an increased apoptosis and greater inhibition of tumor growth and ascites formation. Taken together, our results demonstrate that the antitumor efficacy of JAKi is improved most effectively when combined with SRCi, providing a potential combination strategy for the treatment of advanced ovarian cancer.
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http://dx.doi.org/10.1016/j.tranon.2019.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542771PMC
August 2019

Combination therapy with BYL719 and LEE011 is synergistic and causes a greater suppression of p-S6 in triple negative breast cancer.

Sci Rep 2019 05 17;9(1):7509. Epub 2019 May 17.

Division of Surgical Oncology, City of Hope Comprehensive Cancer Center and Beckman Research Institute, Duarte, CA, USA.

A third of patients with triple negative breast cancer (TNBC) have relapsed disease within 2-5 years from initial diagnosis, leaving an unmet need for therapeutic targets. TNBC frequently harbors alterations of the PI3K/AKT/mTOR pathway, but single agent PI3K/AKT/mTOR inhibitors have not shown marked efficacy. In this study, we investigated a strategy to improve efficacy of PI3K-α inhibitor BYL719 (alpelisib) in TNBC. While BYL719 is effective at inhibiting cell proliferation in T47D, a triple positive cell line, it had limited activity in TNBC. This may be partially due to persistent phosphorylation of RB, and incomplete inhibition of p-S6 in TNBC, since the inhibitory effect of BYL719 on p-RB and p-S6 was significantly reduced in TNBC compared to T47D cells. Addition of the CDK4/6 inhibitor LEE011 to BYL719 caused a simultaneous reduction of p-RB and p-S6, and a more complete inhibition of p-S6, leading to decreased expression of the pro-survival protein MCL-1, an induction of apoptosis, and an enhanced reduction of tumor growth in a PDX model of TNBC. These findings suggest that inhibition of p-RB and p-S6 is important for an effective response to the treatment of TNBC, and provides a strong rationale for clinical development of combination therapy with BYL719 and LEE011 for treatment of metastatic TNBC with intact RB.Presentation: This study was presented in part as an abstract at the 2016 San Antonio Breast Cancer Symposium (P3-03-15) and the 2018 Cancer Research and Targeted Therapy in London.
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http://dx.doi.org/10.1038/s41598-019-43429-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525251PMC
May 2019

Human breast tumor-infiltrating CD8 T cells retain polyfunctionality despite PD-1 expression.

Nat Commun 2018 10 16;9(1):4297. Epub 2018 Oct 16.

Department of Immuno-Oncology, Beckman Research Institute of City of Hope, Duarte, CA, 91010, USA.

Functional CD8 T cells in human tumors play a clear role in clinical prognosis and response to immunotherapeutic interventions. PD-1 expression in T cells involved in chronic infections and tumors such as melanoma often correlates with a state of T-cell exhaustion. Here we interrogate CD8 tumor-infiltrating lymphocytes (TILs) from human breast and melanoma tumors to explore their functional state. Despite expression of exhaustion hallmarks, such as PD-1 expression, human breast tumor CD8 TILs retain robust capacity for production of effector cytokines and degranulation capacity. In contrast, melanoma CD8 TILs display dramatic reduction of cytokine production and degranulation capacity. We show that CD8 TILs from human breast tumors can potently kill cancer cells via bi-specific antibodies. Our data demonstrate that CD8 TILs in human breast tumors retain polyfunctionality, despite PD-1 expression, and suggest that they may be harnessed for effective immunotherapies.
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http://dx.doi.org/10.1038/s41467-018-06653-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191461PMC
October 2018

Sentinel lymph node B cells can predict disease-free survival in breast cancer patients.

NPJ Breast Cancer 2018 23;4:28. Epub 2018 Aug 23.

1Department of Immuno-Oncology, City of Hope and Beckman Research Institute, Duarte, CA USA.

Tumor invasion into draining lymph nodes, especially sentinel lymph nodes (SLNs), is a key determinant of prognosis and treatment in breast cancer as part of the TNM staging system. Using multicolor histology and quantitative image analysis, we quantified immune cells within SLNs from a discovery cohort of 76 breast cancer patients. We found statistically more in situ CD3 T cells in tumor negative vs. tumor positive nodes (mean of 8878 vs. 6704, respectively,  = 0.006), but no statistical difference in CD20 B cells or CD1a dendritic cells. In univariate analysis, a reduced hazard was seen with a unit increase in log CD3 with HR 0.49 (95% CI 0.30-0.80) and log CD20 with HR 0.37 (95% CI 0.22-0.62). In multivariate analysis, log CD20 remained significant with HR 0.42 (95% CI 0.25-0.69). When restricted to SLN tumor negative patients, increased log CD20 was still associated with improved DFS (HR = 0.26, 95% CI 0.08-0.90). The CD20 results were validated in a separate cohort of 21 patients ( = 11 good outcome,  = 10 poor outcome) with SLN negative triple-negative breast cancer (TNBC) ("good" mean of 7011 vs. "poor" mean of 4656,  = 0.002). Our study demonstrates that analysis of immune cells within SLNs, regardless of tumor invasion status, may provide additional prognostic information, and highlights B cells within SLNs as important in preventing future recurrence.
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http://dx.doi.org/10.1038/s41523-018-0081-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107630PMC
August 2018

Identification of Tissue-Specific DNA Methylation Signatures for Thyroid Nodule Diagnostics.

Clin Cancer Res 2019 01 9;25(2):544-551. Epub 2018 Aug 9.

Department of Surgery, City of Hope Comprehensive Cancer Center, Duarte, California.

Purpose: Thyroid cancer is frequently difficult to diagnose due to an overlap of cytologic features between malignant and benign nodules. This overlap leads to unnecessary removal of the thyroid in patients without cancer. While providing some improvement over cytopathologic diagnostics, molecular methods frequently fail to provide a correct diagnosis for thyroid nodules. These approaches are based on the difference between cancer and adjacent thyroid tissue and assume that adjacent tissues are the same as benign nodules. However, in contrast to adjacent tissues, benign thyroid nodules can contain genetic alterations that can be found in cancer. For the development of a new molecular diagnostic test for thyroid cancer, we evaluated DNA methylation in 109 thyroid tissues by using genome-wide single-base resolution DNA methylation analysis. The test was validated in a retrospective cohort containing 65 thyroid nodules.

Results: By conducting reduced representation bisulfite sequencing in 109 thyroid specimens, we found significant differences between adjacent tissue, benign nodules, and cancer. These tissue-specific signatures are strongly linked to active enhancers and cancer-associated genes. Based on these signatures, we developed a new epigenetic approach for thyroid diagnostics. According to the validation cohort, our test has an estimated specificity of 97% [95% confidence interval (CI), 81-100], sensitivity of 100% (95% CI, 87-100), positive predictive value of 97% (95% CI, 83-100), and negative predictive value of 100% (95% CI, 86-100).

Conclusions: These data show that epigenetic testing can provide outstanding diagnostic accuracy for thyroid nodules..
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335179PMC
January 2019

Ruxolitinib synergistically enhances the anti-tumor activity of paclitaxel in human ovarian cancer.

Oncotarget 2018 May 31;9(36):24304-24319. Epub 2018 Jan 31.

Department of Surgery, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.

Treatment for ovarian cancer remains challenging despite a high initial response rate to first line platinum-taxane treatment. Most patients eventually experience recurrence and require further treatment. Persistent activation of STAT3 is associated with cancer growth and progression and is also involved in cell resistance to platinum and taxane treatment. Targeting JAK/STAT3, therefore, could be a potential novel therapeutic approach for treating advanced and chemoresistant ovarian cancer. We investigated the therapeutic potential of ruxolitinib, a JAK1/JAK2 inhibitor that has been FDA-approved for the treatment of myelofibrosis, to treat ovarian cancer either alone or in combination with conventional chemotherapy agents. We show that ruxolitinib inhibits STAT3 activation and ovarian tumor growth both in ovarian cancer cells and in an ovarian cancer mouse model. In addition, ruxolitinib significantly increases the anti-tumor activity of chemotherapy agents, including paclitaxel, cisplatin, carboplatin, doxorubicin and topotecan in ovarian cancer cells. Evaluation of the combination index (CI) shows that ruxolitinib synergistically interacts with paclitaxel in all three human ovarian cancer cells. Finally, our results demonstrate that combination of ruxolitinib and paclitaxel leads to a greater reduction of tumor growth compared to single treatment of either agent in a tumor mouse model that represents late stage ovarian cancer with peritoneal metastasis and ascites formation. Taken together, our findings provide a foundation for clinical trials with ruxolitinib, either as a single agent or in combination with paclitaxel, for the treatment of recurrent and advanced ovarian cancer.
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http://dx.doi.org/10.18632/oncotarget.24368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966246PMC
May 2018

Age greater than 60 years portends a worse prognosis in patients with papillary thyroid cancer: should there be three age categories for staging?

BMC Cancer 2018 03 22;18(1):316. Epub 2018 Mar 22.

Division of Surgical Oncology, Department of Surgery, City of Hope National Medical Center, 1500 East Duarte Rd, Duarte, CA, 91010-8113, USA.

Background: Age is an important prognostic factor in papillary thyroid cancer (PTC), with better survival observed in patients < 45 years of age, regardless of stage. Although the impact of increasing age on PTC-related survival is well-known, previous studies have focused on survival relative to age 45 years only. As the number of patients entering their 7th decade of life increases, PTC-related survival in this demographic becomes increasingly important. Survival in patients ≥ 60 years specifically compared to other groups has not previously been examined. We sought to determine whether age ≥ 60 years is an adverse prognostic factor for disease-specific survival and recurrence in patients with PTC.

Methods: The California Cancer Registry database was linked to inpatient and ambulatory patient records from the Office of Statewide Health Planning and Development for the years 2000-2011. This linked database was queried for patients diagnosed with papillary thyroid cancer and treated with surgery. We then identified prognostic factors related to both 5-year and 10-year disease-specific survival and disease-free survival in patients ≤ 45, 45-59, and ≥ 60 years. Multivariable Cox proportional hazard models were created to test the effect of age ≥ 60 on disease-specific and disease-free survival, controlling for clinical, treatment, and demographic factors.

Results: The final cohort included 15,675 patients. Of the group, 46.3% were between 18 and 44 years of age, 33.6% were 45-59 years, and 20.1% were ≥ 60. Univariate analysis showed that compared to other groups, patients ≥ 60 were more likely to be male (p < 0.001), present with tumors > 5 cm (p < 0.001), more likely to have metastatic disease (p < 0.001), less likely to receive radioactive iodine (p < 0.001), and more likely to receive external beam radiation therapy (p < 0.001). In multivariable Cox proportional hazards models for 5 and 10-year disease-free survival, age ≥ 60 was associated with higher risk of disease at 5 and 10-years (HR 2.3 and 1.9 respectively, p < 0.001). Similar results were observed for 5 and 10-year disease-specific survival (HR 38.0 and 30.0 respectively, p < 0.001) after controlling for gender, race, co-morbidity, stage, surgical procedure, radioactive iodine, insurance, and hospital volume.

Conclusions: Patients ≥ 60 years of age have worse DSS and DFS after a diagnosis of PTC, across all stages of disease. Given that patients over the age of 45 years have progressively worse survival as they age, these data support having three age groups, 18-44 years of age, 45-59 years, and ≥ 60 as an independent predictor of survival and recurrence to current staging guidelines.
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http://dx.doi.org/10.1186/s12885-018-4181-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865378PMC
March 2018

Human brain metastatic stroma attracts breast cancer cells via chemokines CXCL16 and CXCL12.

NPJ Breast Cancer 2017 2;3. Epub 2017 Mar 2.

Department of Immuno-Oncology, City of Hope, Duarte, CA USA.

The tumor microenvironment is composed of heterogeneous populations of cells, including cancer, immune, and stromal cells. Progression of tumor growth and initiation of metastasis is critically dependent on the reciprocal interactions between cancer cells and stroma. Through RNA-Seq and protein analyses, we found that cancer-associated fibroblasts derived from human breast cancer brain metastasis express significantly higher levels of chemokines CXCL12 and CXCL16 than fibroblasts from primary breast tumors or normal breast. To further understand the interplay between cancer cells and cancer-associated fibroblasts from each site, we developed three-dimensional organoids composed of patient-derived primary or brain metastasis cancer cells with matching cancer-associated fibroblasts. Three-dimensional CAF aggregates generated from brain metastasis promote migration of cancer cells more effectively than cancer-associated fibroblast aggregates derived from primary tumor or normal breast stromal cells. Treatment with a CXCR4 antagonist and/or CXCL16 neutralizing antibody, alone or in combination, significantly inhibited migration of cancer cells to brain metastatic cancer-associated fibroblast aggregates. These results demonstrate that human brain metastasis cancer-associated fibroblasts potently attract breast cancer cells via chemokines CXCL12 and CXCL16, and blocking CXCR6-CXCL16/CXCR4-CXCL12 receptor-ligand interactions may be an effective therapy for preventing breast cancer brain metastasis.
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http://dx.doi.org/10.1038/s41523-017-0008-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460196PMC
March 2017

Identification of shared TCR sequences from T cells in human breast cancer using emulsion RT-PCR.

Proc Natl Acad Sci U S A 2016 07 15;113(29):8272-7. Epub 2016 Jun 15.

Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045;

Infiltration of T cells in breast tumors correlates with improved survival of patients with breast cancer, despite relatively few mutations in these tumors. To determine if T-cell specificity can be harnessed to augment immunotherapies of breast cancer, we sought to identify the alpha-beta paired T-cell receptors (TCRs) of tumor-infiltrating lymphocytes shared between multiple patients. Because TCRs function as heterodimeric proteins, we used an emulsion-based RT-PCR assay to link and amplify TCR pairs. Using this assay on engineered T-cell hybridomas, we observed ∼85% accurate pairing fidelity, although TCR recovery frequency varied. When we applied this technique to patient samples, we found that for any given TCR pair, the dominant alpha- or beta-binding partner comprised ∼90% of the total binding partners. Analysis of TCR sequences from primary tumors showed about fourfold more overlap in tumor-involved relative to tumor-free sentinel lymph nodes. Additionally, comparison of sequences from both tumors of a patient with bilateral breast cancer showed 10% overlap. Finally, we identified a panel of unique TCRs shared between patients' tumors and peripheral blood that were not found in the peripheral blood of controls. These TCRs encoded a range of V, J, and complementarity determining region 3 (CDR3) sequences on the alpha-chain, and displayed restricted V-beta use. The nucleotides encoding these shared TCR CDR3s varied, suggesting immune selection of this response. Harnessing these T cells may provide practical strategies to improve the shared antigen-specific response to breast cancer.
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http://dx.doi.org/10.1073/pnas.1606994113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4961128PMC
July 2016

Cinnamon extract reduces VEGF expression via suppressing HIF-1α gene expression and inhibits tumor growth in mice.

Mol Carcinog 2017 02 15;56(2):436-446. Epub 2016 Jun 15.

Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, California.

Although many anti-VEGF agents are available for cancer treatment, side effects of these agents limit their application for cancer treatment and prevention. Here we studied the potential use of a diet-based agent as an inhibitor for VEGF production. Using a VEGF reporter assay, our data showed that an extract from cinnamon (CE) was a potent inhibitor of VEGF production in human cancer cells and suggested inhibition might be mediated through the suppression of HIF-1α gene expression and protein synthesis. Furthermore, CE treatment was found to inhibit expression and phosphorylation of STAT3 and AKT, which are key factors in the regulation of HIF-1α expression, and significantly reduce angiogenesis potential of cancer cells by migration assay. Consistent with these results, we observed significant suppression of VEGF expression, blood vessel formation, and tumor growth in a human ovarian tumor model in mice treated with CE. Cinnamaldehyde, a major component in cinnamon, was identified as one active component in CE that inhibits VEGF expression. Taken together, our findings provide a novel mechanism underlying anti-angiogenic and anti-tumor actions of CE and support the potential use of CE in cancer prevention and treatment. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/mc.22506DOI Listing
February 2017

Characterization of patient-derived tumor xenografts (PDXs) as models for estrogen receptor positive (ER+HER2- and ER+HER2+) breast cancers.

J Steroid Biochem Mol Biol 2017 06 3;170:65-74. Epub 2016 May 3.

Department of Cancer Biology, City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USA. Electronic address:

The research was to appraise the utility of the patient-derived tumor xenografts (PDXs) as models of estrogen receptor positive (ER+HER2- and ER+HER2+) breast cancers. We compared protein expression profiles by Reverse Phase Protein Array (RPPA) in tumors that resulted in PDXs compared to those that did not. Our overall PDX intake rate for ER+ breast cancer was 9% (9/97). The intake rate for ER+HER2+ tumors (3/16, 19%) was higher than for ER+HER2- tumors (6/81, 7%). Heat map analyses of RPPA data showed that ER+HER2- tumors were divided into 2 groups by luminal A/B signature [protein expression of ER, AR, Bcl-2, Bim (BCL2L11), GATA3 and INPP4b], and this expression signature was also associated with the rate of PDX intake. Cell survival pathways such as the PI3K/AKT signaling and RAS/ERK pathways were more activated in the specimens that could be established as PDX in both classes. Expression of the ER protein itself may have a bearing on the potential success of an ER+ PDX model. In addition, HER2 and its downstream protein expressions were up-regulated in the ER+HER2+ patient tumors that were successfully established as PDX models. Moreover, the comparison of RPPA data between original and PDX tumors suggested that the selection/adaptation process required to grow the tumors in mice is unavoidable for generation of ER+ PDX models, and we identified differences between patient tumor samples and paired PDX tumors. A better understanding of the biological characteristics of ER+PDX would be the key to using PDX models in assessing treatment strategies in a preclinical setting.
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http://dx.doi.org/10.1016/j.jsbmb.2016.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5094906PMC
June 2017

IRF-1 inhibits NF-κB activity, suppresses TRAF2 and cIAP1 and induces breast cancer cell specific growth inhibition.

Cancer Biol Ther 2015 ;16(7):1029-41

a Department of Surgery; University of Pittsburgh School of Medicine ; Pittsburgh , PA , USA.

Interferon Regulatory Factor (IRF)-1, originally identified as a transcription factor of the human interferon (IFN)-β gene, mediates tumor suppression and may inhibit oncogenesis. We have shown that IRF-1 in human breast cancer cells results in the down-regulation of survivin, tumor cell death, and the inhibition of tumor growth in vivo in xenogeneic mouse models. In this current report, we initiate studies comparing the effect of IRF-1 in human nonmalignant breast cell and breast cancer cell lines. While IRF-1 in breast cancer cells results in growth inhibition and cell death, profound growth inhibition and cell death are not observed in nonmalignant human breast cells. We show that TNF-α or IFN-γ induces IRF-1 in breast cancer cells and results in enhanced cell death. Abrogation of IRF-1 diminishes TNF-α and IFN-γ-induced apoptosis. We test the hypothesis that IRF-1 augments TNF-α-induced apoptosis in breast cancer cells. Potential signaling networks elicited by IRF-1 are investigated by evaluating the NF-κB pathway. TNF-α and/or IFN-γ results in decreased presence of NF-κB p65 in the nucleus of breast cancer cells. While TNF-α and/or IFN-γ can induce IRF-1 in nonmalignant breast cells, a marked change in NF-κB p65 is not observed. Moreover, the ectopic expression of IRF-1 in breast cancer cells results in caspase-3, -7, -8 cleavage, inhibits NF-κB activity, and suppresses the expression of molecules involved in the NF-κB pathway. These data show that IRF-1 in human breast cancer cells elicits multiple signaling networks including intrinsic and extrinsic cell death and down-regulates molecules involved in the NF-κB pathway.
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http://dx.doi.org/10.1080/15384047.2015.1046646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4622679PMC
June 2016

Synergistic anti-tumor effect of combined inhibition of EGFR and JAK/STAT3 pathways in human ovarian cancer.

Mol Cancer 2015 May 1;14:100. Epub 2015 May 1.

Department of Surgery, Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 East Duarte Rd., Duarte, CA, 91010, USA.

Background: The EGFR signaling pathway is frequently activated in human ovarian cancer and associated with poor prognosis. However, inhibition of EGFR signaling in patients with recurrent ovarian cancer has been disappointing. It remains to be addressed whether ovarian cancer patients could benefit from targeting EGFR signaling. Here we investigated the mechanisms underlying the resistance to EGFR inhibition in ovarian cancer and developed a strategy to overcome it.

Results: We found that treatment of human ovarian cancer cells with an EGFR inhibitor, gefitinib, resulted in increased STAT3 phosphorylation in a dose- and time-dependent manner. Inhibiting STAT3 activation with a small molecule inhibitor of JAK, an upstream kinase that phosphorylates and activates STAT3, synergistically increased the anti-tumor activity of gefitinib in vitro. Similar results were obtained when STAT3 or JAK1 expression was knocked down. In contrast, inhibiting other signaling pathways, such as AKT/mTOR, MEK or SRC, was relatively less effective. The combined treatment resulted in simultaneous attenuation of multiple survival pathways and increased inhibition of ERK pathway. In addition, the dual inhibition showed a stronger suppression of xenograft tumor growth than either single inhibition.

Conclusions: Our findings demonstrate that feedback activation of STAT3 pathway might contribute to the resistance to EGFR inhibition. Combined blockade of both pathways appears to be more effective against human ovarian cancer than inhibition of each pathway alone both in vitro and in vivo. This study may provide a strategy to improve clinical benefit of targeting EGFR pathway in ovarian cancer patients.
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http://dx.doi.org/10.1186/s12943-015-0366-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4437681PMC
May 2015

Baicalein upregulates DDIT4 expression which mediates mTOR inhibition and growth inhibition in cancer cells.

Cancer Lett 2015 Mar 25;358(2):170-179. Epub 2014 Dec 25.

Departments of Surgery, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA. Electronic address:

Baicalein is a natural flavone that exhibits anticancer properties. Using microarrays we found that DDIT4 was the highest transcript induced by baicalein in cancer cells. We confirmed in multiple cancer cell lines large, dose-related expression of DDIT4 by quantitative RT-PCR and immunoblot, which correlates with growth inhibition. Time course experiments demonstrate that DDIT4 is rapidly inducible, with high expression maintained for several days in vitro. Induction of DDIT4 expression is p53 independent based on evaluation of p53 knockout cells. Since DDIT4 is known to inhibit mTORC1 activity we confirmed that baicalein suppresses phosphorylation of mTORC1 targets. Using RNA interference we demonstrate that mTORC1 activity and growth inhibition by baicalein is attenuated by knockdown of DDIT4. We furthermore demonstrate suppression of established tumors by baicalein in a mouse model of breast cancer with increased DDIT4 expression in the tumors. Finally, we demonstrate that baicalein upregulates DDIT4 and causes mTORC1 and growth inhibition in platinum resistant cancer cells in marked contrast to platinum chemotherapy treatment. These studies demonstrate that baicalein inhibits mTORC1 through DDIT4 expression, and may be useful in cancer chemotherapy and chemoprevention.
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http://dx.doi.org/10.1016/j.canlet.2014.12.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989711PMC
March 2015

Pathologic complete response rates in triple-negative, HER2-positive, and hormone receptor-positive breast cancers after anthracycline-free neoadjuvant chemotherapy with carboplatin and paclitaxel with or without trastuzumab.

Breast 2015 Feb 20;24(1):18-23. Epub 2014 Nov 20.

Department of Medical Oncology and Therapeutic Research, City of Hope, 1500 East Duarte Rd., Duarte, CA 91010, USA. Electronic address:

Background: Pathologic complete response (pCR) to neoadjuvant chemotherapy (NCT) is considered a surrogate for improved survival. Platinum-containing NCT, particularly in patients with HER2+ and triple-negative breast cancers (TNBC) may increase pCR rates.

Methods: Tumor characteristics, pCR rates (no invasive disease in breast and lymph nodes), toxicities, and survival in patients who received carboplatin, a taxane, and trastuzumab (HER2+ disease) between April 2009 and December 2011, were reviewed.

Results: Thirty eight patients (39 tumors) completed a median of 4 cycles of NCT. Eighteen of 39 (46%) tumors were HER2+, 8/18 (44%) responded with pCR; 13/18 HER2+ tumors were HR+ (72%) and 4/13 (31%) had a pCR. Ten of 39 (26%) tumors were TNBC; 6/10 (60%) had a pCR. At a median of 25-months no recurrences were observed in patients with pCR.

Conclusions: Prospective studies of anthracycline-free platinum-containing NCT are warranted in LABC patients with HER2+ and TNBC.
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http://dx.doi.org/10.1016/j.breast.2014.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596816PMC
February 2015

Targeting JAK1/STAT3 signaling suppresses tumor progression and metastasis in a peritoneal model of human ovarian cancer.

Mol Cancer Ther 2014 Dec 15;13(12):3037-48. Epub 2014 Oct 15.

Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.

JAK/STAT3 is one of the major signaling pathways that is aberrantly activated in ovarian cancer and associated with tumor progression and poor prognosis in patients with ovarian cancer. In this study, we evaluated the therapeutic potential of targeting JAK/STAT3 signaling in ovarian cancer using a peritoneal dissemination mouse model. We developed this mouse model by injecting a metastatic human ovarian cancer cell line, SKOV3-M-Luc, into the peritoneal cavity of immunodeficient mice. This model displayed a phenotype similar to late-stage ovarian cancer, including extensive peritoneal metastasis and ascites production. The constitutive activation of STAT3 in human ovarian cancer cells appeared to be mediated by an autocrine cytokine loop involving the IL6 family of cytokines and JAK1 kinase. shRNA-mediated knockdown of JAK1 or STAT3 in ovarian cancer cells led to reduced tumor growth, decreased peritoneal dissemination, and diminished ascites production, suggesting a critical role of STAT3 in ovarian cancer progression. Similar results were obtained when a small-molecule inhibitor (JAKi) of the JAK1 kinase was used to treat ovarian cancer in this model. In addition, we found that the expression level of IL6 was correlated with activation of STAT3 in ovarian cancer cells both in vitro and in vivo, suggesting a potential application of IL6 as a biomarker. Altogether, our results demonstrate that targeting JAK1/STAT3, using shRNA knockdown or a small-molecule inhibitor, effectively suppressed ovarian tumor progression and, therefore, could be a potential novel therapeutic approach for treating advanced ovarian cancer.
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http://dx.doi.org/10.1158/1535-7163.MCT-14-0077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4321961PMC
December 2014

IRF-1 regulates alternative mRNA splicing of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in breast epithelial cells generating an immunoreceptor tyrosine-based inhibition motif (ITIM) containing isoform.

Mol Cancer 2014 Mar 21;13:64. Epub 2014 Mar 21.

Departments of Immunology, Beckman Research Institute, City of Hope, Duarte, California, USA.

Background: Interferon regulatory factor-1 (IRF-1) is a master regulator of IFN-γ induced gene transcription. Previously we have shown that IRF-1 transcriptionally induces CEACAM1 via an ISRE (Interferon-Stimulated Response Element) in its promoter. CEACAM1 pre-mRNA undergoes extensive alternative splicing (AS) generating isoforms to produce either a short (S) cytoplasmic domain expressed primarily in epithelial cells or as an ITIM-containing long (L) isoform in immune cells.

Methods: The transcriptional and molecular mechanism of CEACAM1 minigenes AS containing promoter ISREs mutations in the breast epithelial, MDA-MB-468, cell line was detected using flow cytometry. In addition, transcriptome sequencing was utilized to determine whether IRF-1 could direct the AS of other genes as well. Tumor xenografts were used to evaluate CEACAM1 isoform expression on the leading edge of breast tumor cells.

Results: In the present study, we provide evidence that CEACAM1's promoter and variable exon 7 cross-talk allowing IRF-1 to direct AS events. Transcriptome sequencing shows that IRF-1 can also induce the global AS of genes involved in regulation of growth and differentiation as well as genes of the cytokine family. Furthermore, MDA-MB-468 cells grown as tumor xenografts exhibit an AS switch to the L-isoform of CEACAM1, demonstrating that an in vivo inflammatory milieu is also capable of generating the AS switch, similar to that found in human breast cancers Mol Cancer 7:46, 2008.

Conclusions: The novel AS regulatory activities attributed to IRF-1 indicate that the IFN-γ response involves a global change in both gene transcription and AS in breast epithelial cells.
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http://dx.doi.org/10.1186/1476-4598-13-64DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113144PMC
March 2014

Evaluation of expert criteria for preoperative magnetic resonance imaging of newly diagnosed breast cancer.

Breast 2014 Aug 14;23(4):341-5. Epub 2014 Feb 14.

Surgical Oncology, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA. Electronic address:

Despite 2 randomized trials reporting no reduction in operations or local recurrence at 1 year, preoperative magnetic resonance imaging (MRI) is increasingly used in diagnostic workup of breast cancer. We evaluated 5 utilization criteria recently proposed by experts. Of women (n = 340) newly diagnosed with unilateral breast cancer who underwent bilateral MRI, most (69.4%) met at least 1 criterion before MRI: mammographic density (44.4%), under consideration for partial breast irradiation (PBI) (19.7%), genetic-familial risk (12.9%), invasive lobular carcinoma (11.8%), and multifocal/multicentric disease (10.6%). MRI detected occult malignant lesion or extension of index lesion in 21.2% of index, 3.3% of contralateral, breasts. No expert criterion was associated with MRI-detected malignant lesion, which associated instead with pre-MRI plan of lumpectomy without PBI (48.2% of subjects): Odds Ratio 3.05, 95% CI 1.57-5.91 (p adjusted for multiple hypothesis testing = 0.007, adjusted for index-vs-contralateral breast and covariates). The expert guidelines were not confirmed by clinical evidence.
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http://dx.doi.org/10.1016/j.breast.2014.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4074599PMC
August 2014

Interferon Regulatory Factor 1 (IRF-1) induces p21(WAF1/CIP1) dependent cell cycle arrest and p21(WAF1/CIP1) independent modulation of survivin in cancer cells.

Cancer Lett 2012 Jun 23;319(1):56-65. Epub 2011 Dec 23.

Department of Surgery, University of Pittsburgh School of Medicine, 200 Lothrop St., Pittsburgh, PA 15213, USA.

We have shown that the ectopic expression of Interferon Regulatory Factor 1 (IRF-1) results in human cancer cell death accompanied by the down-regulation of the Inhibitor of Apoptosis Protein (IAP) survivin and the induction of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1). In this report, we investigated the direct role of p21 in the suppression of survivin. We show that IRF-1 down-regulates cyclin B1, cdc-2, cyclin E, E2F1, Cdk2, Cdk4, and results in p21-mediated G1 cell cycle arrest. Interestingly, while p21 directly mediates G1 cell cycle arrest, IRF-1 or other IRF-1 signaling pathways may directly regulate survivin in human cancer cells.
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http://dx.doi.org/10.1016/j.canlet.2011.12.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3304016PMC
June 2012

Identification of a natural compound by cell-based screening that enhances interferon regulatory factor-1 activity and causes tumor suppression.

Mol Cancer Ther 2011 Oct 4;10(10):1774-83. Epub 2011 Aug 4.

Department of Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.

The transcription factor interferon regulatory factor-1 (IRF-1) is induced by many tumor-suppressive stimuli and can mediate antiproliferative and proapoptotic effects in cancer cells. Thus, identifying agents that enhance IRF-1 activity may be an effective approach to cancer therapy. A cell-based screening assay was developed to identify extracts and compounds that could enhance IRF-1 activity, using an IRF-1-dependent luciferase reporter cell line. Through this approach, we identified a natural product extract and a known active component of this extract, baicalein, which causes a marked increase in IRF-1-dependent reporter gene expression and IRF-1 protein, with modulation of known IRF-1 targets PUMA and cyclin D1. Baicalein causes suppression of growth in vitro in multiple cancer cell lines in the low micromolar range. IRF-1 plays a role in this growth suppression as shown by significant resistance to growth suppression in a breast cancer cell line stably transfected with short hairpin RNA against IRF-1. Finally, intraperitoneal administration of baicalein by repeated injection causes inhibition of growth in both xenogeneic and syngeneic mouse models of cancer without toxicity to the animals. These findings indicate that identifying enhancers of IRF-1 activity may have utility in anticancer therapies and that cell-based screening for activation of transcription factors can be a useful approach for drug discovery.
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http://dx.doi.org/10.1158/1535-7163.MCT-11-0304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3191301PMC
October 2011

The adrenal mass: correlation of histopathology with imaging.

Ann Surg Oncol 2010 Mar 4;17(3):846-52. Epub 2009 Dec 4.

Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Background: Computed tomography (CT) and magnetic resonance (MR) imaging can help diagnose benign adrenal adenomas, but prior studies rely on nonoperative follow-up as proof of a lesion's benign nature. We examined adrenalectomy tissues to determine if imaging characteristics correlate with histopathologic findings.

Methods: We retrieved data for 196 consecutive adrenalectomies in 192 patients from 2000 to 2008. Imaging results were considered to signify benign adrenal adenoma if one or more of the following was present: Hounsfield units <10 on unenhanced CT, contrast-enhanced CT quantifying absolute contrast washout of >60% or relative contrast washout of >40%, or MR with chemical-shift imaging demonstrating loss of signal intensity on out-of-phase images.

Results: The sensitivity and specificity of preoperative imaging in predicting benign adrenal adenoma were 57 and 94%, respectively. Histopathology confirmed that all 66 adrenal masses with imaging characteristics suggesting benign adenoma were indeed benign lesions and included 61 benign adrenal adenomas and 5 benign nonadenomatous lesions (3 myelolipomas, 1 composite myelolipoma/adenoma, and 1 ganglioliponeuroma). The specificity of imaging in predicting benignity was 100%. Malignant adrenal lesions were diagnosed in 17/130 (13%) masses: 8 metastases, 7 adrenal cortical carcinomas, 1 epithelioid angiosarcoma, and 1 ganglioneuroblastoma. The sensitivity of imaging in identifying malignancy was 100%. No malignancies were diagnosed during postoperative follow-up (mean 6 months, range 0.2-67 months).

Conclusion: CT or MR characteristics predicted the presence of benign lesions with 100% specificity. Every adrenal malignancy had CT or MR results that were inconsistent with benign adenoma (100% sensitivity). To exclude malignancy, adrenal masses with non-benign imaging characteristics should be resected.
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http://dx.doi.org/10.1245/s10434-009-0829-2DOI Listing
March 2010