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1.  A Phase I trial of Bortezomib and Interferon Alfa-2B in Metastatic Melanoma 
The possibility that cytokine administration could enhance the anti-tumor effects of proteasome inhibition was explored. It was found that co-administration of bortezomib and interferon-α (IFN-α) induced synergistic apoptosis in human melanoma cell lines and prolonged survival in a murine model of melanoma. A phase I study was conducted to determine the tolerability and the maximally tolerated dose (MTD) of bortezomib when administered in combination with interferon-α-2b to patients with metastatic melanoma. Patients were treated on a 5 week cycle. In week 1 of cycle 1 patients received 5 MU/m2 IFN-α subcutaneously thrice weekly. During weeks 2–4 of cycle one bortezomib was administered intravenously weekly along with IFN-α thrice weekly. There was a treatment break during week 5. After cycle 1, bortezomib was administered in combination with IFN-α. Bortezomib was administered in escalating doses (1.0, 1.3, or 1.6 mg/m2) to cohorts of three patients. 16 patients were treated (8 female, 8 male; median age 59 years). Common grade 3 toxicities included fatigue (5), vomiting (3), and diarrhea (3). Grade 4 toxicities included fatigue (3) and lymphopenia (1). The MTD for bortezomib was 1.3 mg/m2. One patient had a partial response and 7 had stable disease. Progression-free survival was 2.5 months and overall survival was 10.3 months. Bortezomib administration did not augment the ability of IFN-α to induce phosphorylation of STAT1 in circulating immune cells; however, it did lead to reduced plasma levels of pro-angiogenic cytokines. The combination of bortezomib and IFN-α can be safely administered to melanoma patients.
doi:10.1097/CJI.0000000000000009
PMCID: PMC4174542  PMID: 24316557
Bortezomib; Melanoma; Interferon; Phase I
2.  Intronic miR-3151 Within BAALC Drives Leukemogenesis by Deregulating the TP53 Pathway 
Science signaling  2014;7(321):ra36.
The BAALC/miR-3151 locus on chromosome 8q22 contains both the BAALC gene (for brain and acute leukemia, cytoplasmic) and miR-3151, which is located in intron 1 of BAALC. Older acute myeloid leukemia (AML) patients with high expression of both miR-3151 and the BAALC mRNA transcript have a low survival prognosis, and miR-3151 and BAALC expression is associated with poor survival independently of each other. We found that miR-3151 functioned as the oncogenic driver of the BAALC/miR-3151 locus. Increased production of miR-3151 reduced the apoptosis and chemosensitivity of AML cell lines and increased leukemogenesis in mice. Disruption of the TP53-mediated apoptosis pathway occurred in leukemia cells overexpressing miR-3151 and the miR-3151 bound to the 3′ untranslated region of TP53. In contrast, BAALC alone had only limited oncogenic activity. We found that miR-3151 contains its own regulatory element, thus partly uncoupling miR-3151 expression from that of the BAALC transcript. Both genes were bound and stimulated by a complex of the transcription factors SP1 and nuclear factor κB (SP1/NF-κB). Disruption of SP1/NF-κB binding reduced both miR-3151 and BAALC expression. However, expression of only BAALC, but not miR-3151, was stimulated by the transcription factor RUNX1, suggesting a mechanism for the partly discordant expression of miR-3151 and BAALC observed in AML patients. Similar to the AML cells, in melanoma cell lines, overexpression of miR-3151 reduced the abundance of TP53, and knockdown of miR-3151 increased caspase activity, whereas miR-3151 overexpression reduced caspase activity. Thus, this oncogenic miR-3151 may also have a role in solid tumors.
doi:10.1126/scisignal.2004762
PMCID: PMC4165404  PMID: 24736457
3.  Myeloid Derived Suppressor Cells in Breast Cancer 
Myeloid Derived Suppressor Cells (MDSCs) are a population of immature myeloid cells defined by their suppressive actions on immune cells such as T cells, dendritic cells, and natural killer cells. MDSCs typically are positive for the markers CD33 and CD11b but express low levels of HLADR in humans. In mice, MDSCs are typically positive for both CD11b and Gr1. These cells exert their suppressive activity on the immune system via the production of reactive oxygen species, arginase, and cytokines. These factors subsequently inhibit the activity of multiple protein targets such as the T cell receptor, STAT1, and indoleamine-pyrrole 2,3-dioxygenase. The numbers of MDSCs tend to increase with cancer burden while inhibiting MDSCs improves disease outcome in murine models. MDSCs also inhibit immune cancer therapeutics. In light of the poor prognosis of metastatic breast cancer in women and the correlation of increasing levels of MDSCs with increasing disease burden, the purposes of this review are to 1) discuss why MDSCs may be important in breast cancer, 2) describe model systems used to study MDSCs in vitro and in vivo, 3) discuss mechanisms involved in MDSC induction/function in breast cancer, and 4) present pre-clinical and clinical studies that explore modulation of the MDSC-immune system interaction in breast cancer. MDSCs inhibit the host immune response in breast cancer patients and diminishing MDSC actions may improve therapeutic outcomes.
doi:10.1007/s10549-013-2618-7
PMCID: PMC3773691  PMID: 23828498
Breast Cancer; Myeloid Derived Suppressor Cells; Therapy; Murine models
4.  Review of S100A9 Biology and its Role in Cancer 
Biochimica et biophysica acta  2012;1835(1):100-109.
S100A9 is a calcium binding protein with multiple ligands and post-translation modifications that is involved in inflammatory events and the initial development of the cancer cell through to the development of metastatic disease. This review has a threefold purpose: 1) describe S100A9 structural elements important for its biological activity, 2) describe S100A9 biology in the context of the immune system, and 3) illustrate the role of S100A9 in the development of malignancy via interactions with the immune system and other cellular processes.
doi:10.1016/j.bbcan.2012.10.003
PMCID: PMC3670606  PMID: 23123827
6.  Myeloid derived suppressor cells – a new therapeutic target in the treatment of cancer 
Myeloid Derived Suppressor Cells (MDSC) are a heterogeneous population of immature myeloid cells that are increased in states of cancer, inflammation and infection. In malignant states, MDSC are induced by tumor secreted growth factors. MDSC play an important part in suppression of host immune responses through several mechanisms such as production of arginase 1, release of reactive oxygen species and nitric oxide and secretion of immune-suppressive cytokines. This leads to a permissive immune environment necessary for the growth of malignant cells. MDSC may also contribute to angiogenesis and tumor invasion. This review focuses on currently available strategies to inhibit MDSC in the treatment of cancer.
doi:10.1186/2051-1426-1-10
PMCID: PMC4019895  PMID: 24829747
Myeloid derived suppressor cells; Immunotherapy; Tumor immunology; Cancer vaccines
7.  A Multi-institutional Phase II study of the efficacy and tolerability of Lapatinib in patients with advanced hepatocellular carcinomas 
Background
Hepatocellular carcinoma (HCC) is on the rise worldwide. HCC responds poorly to chemotherapy. Lapatinib is an inhibitor of EGFR and HER2/NEU both implicated in hepatocarcinogenesis. This trial was designed to determine the safety and efficacy of lapatinib in HCC.
Methods
A Fleming phase II design with a single stage of 25 patients with a 90% power to exclude a true response rate of < 10% and detect a true response rate of ≥30% was utilized. The dose of lapatinib was 1,500 mg/d administered orally in 28-day cycles. Tumor and blood specimens were analyzed for expression of HER2/NEU/CEP17 and status of downstream signal pathway proteins.
Results
Twenty-six patients with HCC enrolled on this study. 19% had one prior therapy. Most common toxicities were diarrhea (73%), nausea (54%) and rash (42%). No objective responses were observed. Ten (40%) patients had stable disease (SD) as their best response including 6 (23%) with SD lasting > 120 days. Median progression-free-survival was 1.9 months and median overall survival 12.6 months. Patients who developed a rash had a borderline statistically significant longer survival. Tissue and blood specimens were available on >90% of patients. No somatic mutations in EGFR (exons 18–21) were found. In contrast to our previous findings, we did not find evidence of HER2/NEU somatic mutations. PTEN, P-AKT and P70S6K expression did not correlate with survival.
Conclusions
Lapatinib is well-tolerated but appears to benefit only a subgroup of patients for whom predictive molecular or clinical characteristics are not yet fully defined.
doi:10.1158/1078-0432.CCR-09-0465
PMCID: PMC2774354  PMID: 19737952

Results 1-7 (7)