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George W Sledge

Publications and source records attributed to George W Sledge.

At least 19 recordsLinked to original sources
PubMed2026

Integrated clinicogenomic analysis reveals the evolution and metastatic tropisms of advanced colorectal cancer.

We performed an integrated clinical and genomic analysis of over 7,000 consecutively sequenced colorectal cancer (CRC) samples to comprehensively characterize genetic drivers and metastatic tropisms of CRC. We find that genomic evolutionary changes, such as clonal mutations and oncogenic mutant allelic imbalance, selectively enhance the impact of recurrent oncogenic alterations. We identify the relative timing of organ-specific metastasis, showing sequential metastatic progression in microsatellite stable CRC with brain and adrenal metastases as late events; metastatic sites that cluster together, such as lung, bone, and brain metastases; and genomic events that enhance or decrease risk for each metastatic site, with WNT pathway activation as overall protective while RAS pathway activation increased risk for spread to all metastatic sites. Our data suggest that despite the heterogeneity in CRC, genomic evolution increases the impact of recurrent alterations, and integrating information about tumor primary location and genomics can be used to predict organ-specific metastasis risk.

Humans↗
PubMed2026

Molecular and immune profiling of HER2-low, HER2 ultra-low, and HER2-null male breast cancer.

BACKGROUND: HER2 expression is described along a biological continuum from null to positive and serves as a critical biomarker for therapeutic guidance in breast cancer (BC). While HER2-low and ultra-low categories have emerged as actionable targets for antibody-drug conjugates (ADCs) in female BC, their molecular and immune characteristics remain largely unexplored in male breast cancer. METHODS: We profiled 214 male breast tumors using next-generation sequencing and whole-transcriptome sequencing to assess mutational, transcriptomic, and immune landscapes. Tumor mutational burden (TMB) was defined as high if > 10 mutations/Mb. Immune cell fractions were inferred using Quantiseq deconvolution. RESULTS: Among 214 samples, 66 (30.8%) were HER2-null, 53 (24.8%) HER2 ultra-low, 80 (37.4%) HER2-low, and 15 (7.0%) HER2-positive. HER2 ultra-low tumors exhibited a higher prevalence of PIK3CA mutations (39.2% vs 22.6%, p ≤ 0.05) compared to HER2-null. No significant differences were observed in TMB-high frequency or PD-L1 expression across subgroups. Immune composition differed primarily between HER2-null and HER2-expressing subgroups: HER2-ultra-low tumors showed higher B-cell infiltration, whereas HER2-null tumors were enriched in neutrophils. Transcriptomic analysis revealed upregulation of selected stemness-associated genes (NANOG, KLF4, POU5F1) and CEACAM1 in HER2-null tumors, while HER2-low and HER2-ultra-low tumors were largely similar across most molecular and immune readouts in this cohort. CONCLUSIONS: HER2-null male breast cancer appears to represent the most biologically divergent subgroup within the HER2-negative spectrum, whereas HER2-low and HER2-ultra-low tumors were largely similar in this cohort. These findings support further investigation of HER2-null disease as a distinct biological state and provide hypothesis-generating data for biomarker development in this rare population.

Male↗
PubMed2006

p27(Kip1) and cyclin E expression and breast cancer survival after treatment with adjuvant chemotherapy.

BACKGROUND: Abnormal expression of the cell cycle regulatory proteins p27(Kip1) (p27) and cyclin E may be associated with breast cancer survival and relapse. We studied these markers in a clinical trial setting with patients with breast cancer treated by a uniform drug regimen so that treatment was not associated with variability in outcome. METHODS: We used tissue microarrays to evaluate the expression of p27 and cyclin E proteins by immunohistochemistry in tumor tissue from 2123 (68%) of 3122 patients with moderate-risk primary breast cancer who were enrolled in Southwest Oncology Group-Intergroup Trial S9313, in which patients were assigned to receive doxorubicin and cyclophosphamide administered concurrently (n = 1595) or sequentially (n = 1527). Disease-free and overall survival were equivalent in the two arms. Expression of the proteins was rated on a scale of 1-7, and the median value was used as the cut point. Log-rank tests and Cox regression analyses were used to assess associations with survival. Overall survival was defined as time to death from all causes; disease-free survival was defined as time to recurrence or death. All P values were from two-sided statistical tests. RESULTS: Lower p27 expression was associated with worse overall survival (unadjusted hazard ratio [HR] = 1.50, 95% confidence interval [CI] = 1.21 to 1.86) and disease-free survival (unadjusted HR = 1.31, 95% CI = 1.10 to 1.57) than higher p27 expression. Among hormone receptor-positive patients, lower p27 expression was associated with worse overall survival (HR = 1.42, 95% CI = 1.05 to 1.94) and worse disease-free survival (HR = 1.27, 95% CI = 0.99 to 1.63) than higher p27 expression after adjustment for treatment, menopausal status, tumor size, and number of positive lymph nodes. Among these patients, 5-year overall survival associated with higher p27 expression (0.91, 95% CI = 0.89 to 0.93) was similar to that associated with lower p27 expression (0.85, 95% CI = 0.82 to 0.87). No association between p27 expression and survival was found in hormone receptor-negative patients. Cyclin E expression was not statistically significantly associated with overall survival (HR = 1.12, 95% CI = 0.91 to 1.38) or disease-free survival (HR = 1.09, 95% CI = 0.92 to 1.29). CONCLUSIONS: Low p27 expression appears to be associated with poor prognosis, especially among patients with steroid receptor-positive tumors.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Synthesis of carbon-11 labeled sulfonanilide analogues as new potential PET agents for imaging of aromatase in breast cancer.

Aromatase is a particularly good target in the treatment of estrogen receptor positive breast cancer. Novel carbon-11 labeled sulfonanilide analogues, N-[11C]methyl-N-(2-alkyloxy-4-nitrophenyl)-methanesulfonamides ([11C]3a-f, alkyl=propyl, isopropyl, 1-ethyl-propyl, cyclopentyl, cyclohexyl, and cyclohexylethyl), were designed and synthesized as potential PET agents for imaging of aromatase in breast cancer.

Adult↗
PubMed2006

Predicting response to primary chemotherapy: gene expression profiling of paraffin-embedded core biopsy tissue.

PURPOSE: Primary chemotherapy provides an ideal opportunity to correlate gene expression with response to treatment. We used paraffin-embedded core biopsies from a completed phase II trial to identify genes that correlate with response to primary chemotherapy. PATIENTS AND METHODS: Patients with newly diagnosed stage II or III breast cancer were treated with sequential doxorubicin 75 mg/M2 q2 wks x 3 and docetaxel 40 mg/M2 weekly x 6; treatment order was randomly assigned. Pretreatment core biopsy samples were interrogated for genes that might correlate with pathologic complete response (pCR). In addition to the individual genes, the correlation of the Oncotype DX Recurrence Score with pCR was examined. RESULTS: Of 70 patients enrolled in the parent trial, core biopsies samples with sufficient RNA for gene analyses were available from 45 patients; 9 (20%) had inflammatory breast cancer (IBC). Six (14%) patients achieved a pCR. Twenty-two of the 274 candidate genes assessed correlated with pCR (p < 0.05). Genes correlating with pCR could be grouped into three large clusters: angiogenesis-related genes, proliferation related genes, and invasion-related genes. Expression of estrogen receptor (ER)-related genes and Recurrence Score did not correlate with pCR. In an exploratory analysis we compared gene expression in IBC to non-inflammatory breast cancer; twenty-four (9%) of the genes were differentially expressed (p < 0.05), 5 were upregulated and 19 were downregulated in IBC. CONCLUSION: Gene expression analysis on core biopsy samples is feasible and identifies candidate genes that correlate with pCR to primary chemotherapy. Gene expression in IBC differs significantly from noninflammatory breast cancer.

Adult↗
PubMed2006

Restoring chemotherapy and hormone therapy sensitivity by parthenolide in a xenograft hormone refractory prostate cancer model.

BACKGROUND: Nuclear Factor kappa B (NFkappaB) is a eukaryotic transcription factor that is constitutively active in human cancers and can be inhibited by the naturally occurring sesquiterpene lactone, parthenolide (P). METHODS: The in vitro effects of P were assessed using the androgen independent cell line, CWR22Rv1, and human umbilical endothelial cells (HUVECs). The in vivo activity of P as a single agent and its ability to augment the efficacy of docetaxel and the anti-androgen, bicalutamide, were determined using the CWR22Rv1 xenograft model. RESULTS: Parthenolide at low micromolar concentration inhibited proliferation of CWR22Rv1 and HUVEC cells, promoted apoptosis and abrogated NFkappaB-DNA binding. Parthenolide downregulated anti-apoptotic genes under NFkappaB control, TRAF 1 and 2, and promoted sustained activation of c-jun-NH2 kinase (JNK). Parthenolide also augmented the in vivo efficacy of docetaxel and restored sensitivity to anti-androgen therapy. CONCLUSION: These studies demonstrate parthenolide's anti-tumor and anti-angiogenic activity, and its potential to augment the efficacy of chemotherapy and hormonal therapy.

Androgen Antagonists↗
PubMed2006

Phase I safety, pharmacokinetic and pharmacodynamic studies of 2-methoxyestradiol alone or in combination with docetaxel in patients with locally recurrent or metastatic breast cancer.

PURPOSE: We report the first phase I trials of 2-methoxyestradiol (2ME2, Panzem Capsules, EntreMed, Rockville, MD), alone and in combination with docetaxel, in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: In Trial 001, 2ME2 monotherapy was administered orally once (200-1000 mg/d, cohorts 1-5) or twice daily (200-800 mg/q12h, cohorts 6-9) for 28 days followed by a 14-day observation period, continuously thereafter. In Trial 002, docetaxel 35 mg/m(2) was administered weekly for four of six weeks for a maximum six cycles; 2ME2 (200-1000 mg/d) was given orally once daily for 28 days followed by a 13-day observation period in cycle one, continuously thereafter. In both trials, responding or stable patients continued 2ME2 until progression. RESULTS: Trial 001 enrolled 31 patients; there were no objective responses. Trial 002 enrolled 15 patients; ORR was 20% including one CR. There were no Grade IV toxicities; MTD was not reached in either study. When combined with docetaxel, three patients had significant transaminase elevations that returned to normal with continued treatment (in two of three patients). There was significant inter-patient variability and extensive metabolism to 2-methoxyestrone (2ME1). Steady-state AUC and trough concentrations of 2ME2 increased linearly up to 400-600 mg/d; doses above 400-600 mg/d did not increase 2ME2 levels. The target trough concentration (3-25 ng/mL) was not attained. Combined administration did not alter docetaxel or 2ME2 pharmacokinetics. CONCLUSION: 2ME2, alone or in combination with docetaxel, was well tolerated in patients with MBC but systemic exposure remained below the expected therapeutic range.

2-Methoxyestradiol↗
PubMed2006

Synthesis of carbon-11 labeled fluorinated 2-arylbenzothiazoles as novel potential PET cancer imaging agents.

Fluorinated 2-arylbenzothiazoles are new potential antitumor drugs, which show potent and selective inhibitory activity against breast, lung, and colon cancer cell lines. Carbon-11 labeled fluorinated 2-arylbenzothiazoles may serve as novel probes for positron emission tomography (PET) to image tyrosine kinase in cancers. The preparation of 4-fluorinated 2-arylbenzothiazoles 4-fluoro-2-(3-benzloxy-4-methoxyphenyl)benzothiazole (6a) and 4-fluoro-2-(3,4-dimethoxyphenyl)benzothiazole (6b) was achieved by a modification of Jacobson thioanilide radical cyclization chemistry. Hydrogenolytic cleavage of the benzyl ether group of compound 6a using H(2)/Pd-C provided the precursor 4-fluoro-2-(3-hydroxy-4-methoxyphenyl)benzothiazole (7) for radiolabeling. Synthesis of radiolabeling precursors and the reference standards 5- and 6-fluorinated arylbenzothiazoles (11c-n) was achieved via the reaction of o-aminothiophenol disulfides with substituted benzaldehydes under reducing conditions. The target radiotracers carbon-11 labeled 4-, 5-, and 6-fluorinated arylbenzothiazoles (3-[(11)C]6b, 4-[(11)C]11c, 3-[(11)C]11c, 5-[(11)C]11f, 4-[(11)C]11f, 4-[(11)C]11i, 3-[(11)C]11i, 5-[(11)C]11l, and 4-[(11)C]11l) were prepared by O-[(11)C]methylation of the phenolic hydroxyl precursors (7, 11d, 11e, 11g, 11h, 11j, 11k, 11m, and 11n) with [(11)C]methyl triflate and isolated by solid-phase extraction (SPE) purification in 30-55% radiochemical yields.

Animals↗
PubMed2006

Synthesis of radiolabeled stilbene derivatives as new potential PET probes for aryl hydrocarbon receptor in cancers.

New carbon-11 and fluorine-18 labeled stilbene derivatives, cis-3,5-dimethoxy-4'-[11C]methoxystilbene (4'-[11C]8a), cis-3,4',5-trimethoxy-3'-[11C]methoxystilbene (3'-[11C]8b), trans-3,5-dimethoxy-4'-[11C]methoxystilbene (4'-[11C]10a), trans-3,4',5-trimethoxy-3'-[11C]methoxystilbene (3'-[11C]10b), cis-3,5-dimethoxy-4'-[18F]fluorostilbene (4'-[18F]12a), and trans-3,5-dimethoxy-4'-[18F]fluorostilbene (4'-[18F]13a), were designed and synthesized as potential PET probes for aryl hydrocarbon receptor (AhR) in cancers.

Animals↗
PubMed2006

Telomerase template antagonist GRN163L disrupts telomere maintenance, tumor growth, and metastasis of breast cancer.

PURPOSE: Maintenance of telomeres by telomerase is critical for the continuing proliferation of most advanced cancer cells. Telomerase activity has been detected in the vast majority of cancer cells but not most normal cells, making the enzyme an attractive target for anticancer therapy. The aim of this study was to address the breast cancer translational potential of the novel telomerase inhibitor, GRN163L. EXPERIMENTAL DESIGN: In the present study, we investigated the effects of GRN163L treatment on a panel of breast cancer cells representing different tumor subtypes with varying genetic backgrounds, including ER+, ER-, HER2+, BRCA1 mutant breast tumor cells as well as doxorubicin-resistant cancer cells. To investigate the in vivo effects of GRN163L, we employed a breast cancer xenograft and metastasis model that simulates a clinical situation in which a patient arrives with a primary tumor that may be then treated or surgically removed. RESULTS: GRN163L effectively inhibited telomerase activity in a dose-dependent fashion in all breast cancer cell lines resulting in progressive telomere shortening. A mismatch control oligonucleotide showed no effect on telomerase activity and GRN163L did not significantly affect telomere shortening in normal human mammary epithelial cells or in endothelial cells. Breast cancer cells that exhibited telomerase inhibition also exhibited significant reduction in colony formation and tumorigenicity. Furthermore, GRN163L suppressed tumor growth and lung metastases (P = 0.017) of MDA-MB-231 cells in vivo after 4 weeks of treatment. CONCLUSIONS: These results show in vivo effectiveness of GRN163L in breast cancer and support its promising clinical potential for breast cancer treatment.

Adenocarcinoma↗
PubMed2006

Synthesis of [11C]Iressa as a new potential PET cancer imaging agent for epidermal growth factor receptor tyrosine kinase.

Iressa (Gefitinib) is an orally active inhibitor of epidermal growth factor receptor tyrosine kinase (EGFR-TK) involved in cell signal transduction processes critical to proliferation, apoptosis, repair, and angiogenesis of cancer cells. [11C]Iressa was first designed and synthesized as a new potential positron emission tomography (PET) cancer imaging agent for EGFR-TK in 30-40% radiochemical yield with 4.0-6.0 Ci/micromol specific activity at end of bombardment (EOB).

Antineoplastic Agents↗
PubMed2006

Effects of HIV protease inhibitor ritonavir on Akt-regulated cell proliferation in breast cancer.

PURPOSE: These studies were designed to determine whether ritonavir inhibits breast cancer in vitro and in vivo and, if so, how. EXPERIMENTAL DESIGN: Ritonavir effects on breast cancer cell growth were studied in the estrogen receptor (ER)-positive lines MCF7 and T47D and in the ER-negative lines MDA-MB-436 and MDA-MB-231. Effects of ritonavir on Rb-regulated and Akt-mediated cell proliferation were studied. Ritonavir was tested for inhibition of a mammary carcinoma xenograft. RESULTS: ER-positive estradiol-dependent lines (IC50, 12-24 micromol/L) and ER-negative (IC50, 45 micromol/L) lines exhibit ritonavir sensitivity. Ritonavir depletes ER-alpha levels notably in ER-positive lines. Ritonavir causes G1 arrest, depletes cyclin-dependent kinases 2, 4, and 6 and cyclin D1 but not cyclin E, and depletes phosphorylated Rb and Ser473 Akt. Ritonavir induces apoptosis independent of G1 arrest, inhibiting growth of cells that have passed the G1 checkpoint. Myristoyl-Akt, but not activated K-Ras, rescues ritonavir inhibition. Ritonavir inhibited a MDA-MB-231 xenograft and intratumoral Akt activity at a clinically attainable serum Cmax of 22 +/- 8 micromol/L. Because heat shock protein 90 (Hsp90) substrates are depleted by ritonavir, ritonavir effects on Hsp90 were tested. Ritonavir binds Hsp90 (K(D), 7.8 micromol/L) and partially inhibits its chaperone function. Ritonavir blocks association of Hsp90 with Akt and, with sustained exposure, notably depletes Hsp90. Stably expressed Hsp90alpha short hairpin RNA also depletes Hsp90, inhibiting proliferation and sensitizing breast cancer cells to low ritonavir concentrations. CONCLUSIONS: Ritonavir inhibits breast cancer growth in part by inhibiting Hsp90 substrates, including Akt. Ritonavir may be of interest for breast cancer therapeutics and its efficacy may be increased by sustained exposure or Hsp90 RNA interference.

Animals↗
PubMed2006

Analysis of angiogenesis genes from paraffin-embedded breast tumor and lymph nodes.

BACKGROUND: Angiogenesis is important in tumor growth and metastasis. Germ-line polymorphisms critical to the angiogenesis pathway have been shown to confer prognostic information in multiple tumor types. These genes include vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS). EXPERIMENTAL DESIGN: We extracted DNA from 53 specimens obtained from 21 patients including a primary breast tumor, and/or a histologically involved lymph node, and/or a histologically normal lymph node. We subsequently genotyped all specimens to evaluate two polymorphisms in the eNOS gene and one polymorphism in the VEGF gene. RESULTS: Chromatographs were generated in 145/159 (91%) samples. When assessing all polymorphisms by site, chromatographs were generated in 42/51 (83%) samples obtained from the primary tumor and 103/108 (95%) from lymph nodes. Chromatographs were generated in 46/53 (87%) samples from the T(-786)C polymorphism in the 5'-flanking region in the eNOS gene, 49/53 (92%) when assessing the Glu298Asp polymorphism in exon 7 in the eNOS gene and 50/53 samples (94%) for the C(936)T polymorphism in the VEGF gene. There was 100% concordance between analyses from the primary tumor, uninvolved lymph node, and involved lymph node from the same case. CONCLUSION: We successfully extracted DNA and genotyped several polymorphisms in two genes important in angiogenesis. These genotypes were determined in breast tumors, but also in involved and uninvolved lymph nodes. There was concordance between the genotypes of germline DNA obtained from uninvolved lymph nodes and those determined in tumor samples, implying that the host angiogenic genotype imprints the tumor genotype.

Breast Neoplasms↗
PubMed2006

A physiologic imaging pilot study of breast cancer treated with AZD2171.

BACKGROUND: This pilot study combined physiologic imaging, microcomputed tomography, and histologic tumor evaluation with a xenograft model of breast cancer to identify surrogates likely to correlate with response to AZD2171, an inhibitor of the vascular endothelial growth factor (VEGF) receptor tyrosine kinases. EXPERIMENTAL DESIGN: MCF-7 cells transfected with vector (MCF-7neo) or VEGF (MCF(VEGF)) were implanted in the right and left mammary fat pads of 75 athymic mice. Treatment with AZD2171 (5 mg/kg/d) or vehicle control was initiated once tumors were established. Positron emission tomography with [11C]carbon monoxide to measure blood volume, [18F]fluoromethane to measure perfusion, and [18F]fluorodeoxyglucose to measure glucose utilization was done at baseline, and after 24 hours, 72 hours, and 4 weeks of treatment. After imaging, tumors were analyzed for microvessel density, proliferation, and VEGF expression. RESULTS: AZD2171 induced significant inhibition of tumor growth in established MCF-7(neo) xenografts and regression of established MCF-7(VEGF) xenografts. An acute decrease in blood flow was detected in MCF-7(VEGF) tumors at 24 hours (P = 0.05). Tumor blood volume was increased in the MCF-7(VEGF) tumors but correlated with tumor size; blood volume did not change with AZD2171 therapy. Glucose utilization correlated with tumor size and did not change with acute or chronic AZD2171 therapy. Unlike blood flow and blood volume, glucose utilization was similar in MCF-7neo and MCF-7(VEGF) tumors. Microvessel density and proliferation acutely decreased in MCF-7(VEGF) tumors but returned to baseline during chronic therapy. CONCLUSIONS: [18F]Fluoromethane imaging may be a useful surrogate for biological activity of AZD2171 with changes identified within 24 hours of starting therapy.

Angiogenesis Inhibitors↗
PubMed2006

Protein kinase C-beta as a therapeutic target in breast cancer.

Combining existing breast cancer therapies with novel agents that interfere with major signaling pathways is a promising approach. Targeting protein kinase C (PKC)-beta may serve as an attractive candidate in this regard for the following reasons: first, PKC-beta II (a splice variant of PKC-beta) has been implicated in tumorigenesis in human and rodent models. Second, PKC-beta, mainly PKC-betaII, is the predominant mediator of vascular endothelial growth factor-induced endothelial cell proliferation, which is a well-known stimulator of tumor angiogenesis and growth in breast cancer. There is increasing evidence that PKC-beta-selective inhibitors are effective in both preclinical and clinical trials. Enzastaurin, a potent inhibitor of PKC-beta, suppresses both tumor growth and tumor-induced angiogenesis in human tumor xenografts. Phase II trials of enzastaurin in recurrent high-grade gliomas and lymphomas have shown promising results. A similar compound, ruboxistaurin, is also under investigation in clinical trials for diabetic complications. This review focuses on the rationale for using PKC-beta as a therapeutic target at both the preclinical and clinical levels in breast cancer.

Breast Neoplasms↗