Search

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment. Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered.

Abstract Background Advanced cancer and chemotherapy are both associated with immune system suppression. We initiated a clinical trial in patients receiving chemotherapy for metastatic colorectal cancer to determine if administration of GM-CSF in this setting was immunostimulatory. Methods Between June, 2003 and January, 2007, 20 patients were enrolled in a clinical trial (NCT00257322) in which they received 500 ug GM-CSF daily for 4 days starting 24 hours after each chemotherapy cycle. There were no toxicities or adverse events reported. Blood was obtained before chemotherapy/GM-CSF administration and 24 hours following the final dose of GM-CSF and evaluated for circulating dendritic cells and adaptive immune cellular subsets by flow cytometry. Peripheral blood mononuclear cell (PBMC) expression of γ-interferon and T-bet transcription factor (Tbx21) by quantitative real-time PCR was performed as a measure of Th1 adaptive cellular immunity. Pre- and post-treatment (i.e., chemotherapy and GM-CSF) samples were evaluable for 16 patients, ranging from 1 to 5 cycles (median 3 cycles, 6 biologic sample time points). Dendritic cells were defined as lineage (-) and MHC class II high (+). Results 73% of patients had significant increases in circulating dendritic cells of ~3x for the overall group (5.8% to 13.6%, p = 0.02) and ~5x excluding non-responders (3.2% to 14.5%, p < 0.001). This effect was sustained over multiple cycles for approximately half of the responders, but tachyphylaxis over subsequent chemotherapy cycles was noted for the remainder. Treatment also led to a significant reduction in the proportion of circulating regulatory T-cells (Treg; p = 0.0042). PBMC Tbx21 levels declined by 75% following each chemotherapy cycle despite administration of GM-CSF (p = 0.02). PBMC γ-interferon expression, however was unchanged. Conclusions This clinical trial confirms the suppressive effects of chemotherapy on Th1 cellular immunity in patients with metastatic colorectal cancer but demonstrates that mid-cycle administration of GM-CSF can significantly increase the proportion of circulating dendritic cells. As the role of dendritic cells in anti-tumor immunity becomes better defined, GM-CSF administration may provide a non-toxic intervention to augment this arm of the immune system for cancer patients receiving cytotoxic therapy. Trial Registration ClinicalTrials.gov: NCT00257322

While the role of Wnt signaling is well established in colorectal carcinogenesis, its function in gynecologic cancers has not been elucidated. Here, we describe the current state of knowledge of canonical Wnt signaling in endometrial cancer (EC), and its implications for future therapeutic targets. Deregulation of the Wnt/β-catenin signaling pathway in EC occurs by inactivating β-catenin mutations in approximately 10-45% of ECs, and via downregulation of Wnt antagonists by epigenetic silencing. The Wnt pathway is intimately involved with estrogen and progesterone, and emerging data implicate it in other important signaling pathways, such as mTOR and Hedgehog. While no therapeutic agents targeting the Wnt signaling pathway are currently in clinical trials, the preclinical data presented suggest a role for Wnt signaling in uterine carcinogenesis, with further research warranted to elucidate the mechanism of action and to proceed towards targeted cancer drug development.

Potentially favorable effects of wine consumption on colorectal cancer (CRC) incidence have been reported, but effects on clinical outcomes are unknown. This case-only analysis was designed to investigate outcomes among familial (n = 141) and sporadic (n = 358) CRC patients enrolled in the University of California Irvine CRC gene-environment study during 1994-1996 based on their reported frequency of wine consumption in the year prior to diagnosis. Cases were categorized as either regular or infrequent wine consumers. Univariate survival rate analyses were estimated using the Kaplan and Meier method and log-rank test. Multivariate survival analyses were performed using Cox proportional hazards ratios (HRs). Earlier stage at presentation (P = 0.034) was noted for familial (but not sporadic) CRC cases reporting regular wine consumption. An overall survival (OS) benefit was observed for familial (but not sporadic) CRC cases that were regular (10-yr OS = 75%) versus infrequent wine consumers (10-yr OS = 47%; P = 0.002). This survival improvement for familial CRC cases remained after adjustment for age, stage, treatment, and other clinically relevant factors (HR = 0.50, 95% confidence interval = 0.25-0.99). Our findings implicate favorable effects of wine consumption on stage at presentation and survival in CRC, selectively among familial CRC cases.

BackgroundNorrin is a potent Wnt pathway ligand. Aberrant activation of this signaling pathway can result in colon tumors but the role of norrin-based signaling in the genesis of colon cancer, and its relationship to activation of the pathway by traditional Wnt ligands, is not defined.ResultsFresh normal human colon tissue and all the cell lines studied expressed mRNA for Fz4, LRP5 and norrin, except Colo205 which lacked Fz4 expression. Canonical Wnt pathway throughput was increased slightly in NCM460 following treatment with Wnt3a CM but was inhibited by Wnt2 and Wnt1. The colon cancer cell line, RKO, responded to Wnt3a CM, Wnt2 and Wnt1 by increasing canonical Wnt pathway throughput. Wnt5a did not affect Wnt pathway throughput in either cell line. Wnt2, but not Wnt3a, abrogated Fz4 expression in NCM460, but not in RKO or another colon cancer cell line, HCT116. This effect on Fz4 was confirmed at both the RNA and protein levels via RT-PCR and a norrin binding assay. The expression of all others 9 Fz receptors did not change after treatment of NCM460 cells with Wnt2.ConclusionThe data suggests that colonic mucosa and colon tumors may possess two autoregulatory positive Wnt feedback loops, one through canonical signals induced by Wnt:Fz interactions and one through signals resulting from norrin:Fz4 interactions. The latter interactions may be modulated via regulation of Fz4 expression by Wnt2. Retention of Fz4 by cancers, in contrast to the loss of Fz4 by normal mucosal cells, could provide a selective advantage to the tumor cells. Fz4 expression may play a critical role in responses to Wnt signaling in the tumor microenvironment.

Rationale and objectivesNear-infrared (NIR) diffuse optical spectroscopy and imaging may enhance existing technologies for breast cancer screening, diagnosis, and treatment. NIR techniques are based on sensitive, quantitative measurements of functional contrast between healthy and diseased tissue. In this study, the authors quantified the origins of this contrast in healthy breasts.Materials and methodsA seven-wavelength frequency-domain photon migration probe was used to perform noninvasive NIR measurements in the breasts of 28 healthy women, both pre- and postmenopausal, aged 18-64 years. A diffusive model of light transport quantified oxygenated and deoxygenated hemoglobin, water, and lipid by their absorption signatures. Changes in the measured light-scattering spectra were quantified by means of a "scatter power" parameter.ResultsSubstantial quantitative differences were observed in both absorption and scattering spectra of breast as a function of subject age. These physiologic changes were consistent with long-term hormone-dependent transformations that occur in breast. Instrument response was not adversely affected by subject age or menopausal status.ConclusionThese measurements provide new insight into endogenous optical absorption and scattering contrast mechanisms and have important implications for the development of optical mammography. NIR spectroscopy yields quantitative functional information that cannot be obtained with other noninvasive radiologic techniques.

PURPOSE Although effective care coordination (CC) is recognized as a vital component of a patient-centered, high-quality cancer care delivery system, CC experiences of patients who enroll and receive treatment through clinical trials (CTs) are relatively unknown. Using mixed methods, we examined perceptions of CC among patients enrolled onto therapeutic CTs through the Hawaii Minority/Underserved National Cancer Institute Community Oncology Research Program. METHODS The Care Coordination Instrument, a validated instrument, was used to measure patients’ perceptions of CC among CT participants (n 5 45) and matched controls (n 5 45). Paired t-tests were used to compare overall and three CC domain scores (Communication, Navigation, and Operational) between the groups. Semistructured focus group interviews were conducted virtually with 14 CT participants in 2020/2021. RESULTS CT participants reported significantly higher total CC scores than non-CT participants (P 5 .0008). Similar trends were found for Navigation and Operational domain scores (P 5 .007 and .001, respectively). Twenty-nine percent of CT participants reported receiving high-intensity CC assistance from their clinical research professionals (CRPs). Content analysis of focus group discussions revealed that nearly half of the focus group discussions centered on CRPs (47%), including CC support provided by CRPs (26%). Other key themes included general CT experiences (22%) and CRP involvement as an additional benefit to CT participation (15%). CONCLUSION Our results show that patients on CTs in this study had a more positive CC experience. This may be attributable in part to CC support provided by CRPs. These findings highlight both the improved experience of treatment for patients participating in a trial and the generally unrecognized yet integral role of CRPs as part of a cancer CT care team. [ABSTRACT FROM AUTHOR]