TGF-β signaling in cancer – a double-edged sword

Transforming growth factor-beta (TGF-β) is a multifunctional regulatory polypeptide that is the prototypical member of a large family of cytokines that controls many aspects of cellular function, including cellular proliferation, differentiation, migration, apoptosis, adhesion, angiogenesis, immune surveillance, and survival. The actions of TGF-β are dependent on several factors including cell type, growth conditions, and the presence of other polypeptide growth factors. One of the biological effects of TGF-β is the inhibition of proliferation of most normal epithelial cells using an autocrine mechanism of action, and this suggests a tumor suppressor role for TGF-β. Loss of autocrine TGF-β activity and/or responsiveness to exogenous TGF-β appears to provide some epithelial cells with a growth advantage leading to malignant progression. This suggests a pro-oncogenic role for TGF-β in addition to its tumor suppressor role. During the early phase of epithelial tumorigenesis, TGF-β inhibits primary tumor development and growth by inducing cell cycle arrest and apoptosis. In late stages of tumor progression when tumor cells become resistant to growth inhibition by TGF-β due to inactivation of the TGF-β signaling pathway or aberrant regulation of the cell cycle, the role of TGF-β becomes one of tumor promotion. Resistance to TGF-β-mediated inhibition of proliferation is frequently observed in multiple human cancers, as are various alterations in the complex TGF-β signaling and cell cycle pathways. TGF-β can exert effects on tumor and stromal cells as well as alter the responsiveness of tumor cells to TGF-β to stimulate invasion, angiogenesis, and metastasis, and to inhibit immune surveillance. Because of the dual role of TGF-β as a tumor suppressor and pro-oncogenic factor, members of the TGF-β signaling pathway are being considered as predictive biomarkers for progressive tumorigenesis, as well as molecular targets for prevention and treatment of cancer and metastasis.

Transforming growth factor-β in cancer and metastasis

The concept of contrast imaging was introduced to ultrasound almost 30 years ago. The development of ultrasound contrast agents (USCAs), initially slowed by technical limitations, has become more dynamic during the past decade. The ideal USCA should be non-toxic, injectable intravenously, capable of crossing the pulmonary capillary bed after a peripheral injection, and stable enough to achieve enhancement for the duration of the examination. While satisfying cost–benefit requirements, it should provide not only Doppler but also gray-scale enhancement. Already, Doppler examinations are improved by using USCAs when studying deep and small vessels, vessels with low or slow flow, or vessels with a non-optimal insonation angle. Ultrasound contrast agents also enhance detection of flow within abnormal vessels, including tumor vascularization and stenotic vessels, and provide better delineation of ischemic areas. Research is focusing on the development of specific contrast imaging sequences that allow detection of tissue enhancement similar to that obtained with CT or MRI. These sequences take advantage of the non-linear behavior of the microbubbles within the ultrasound field, bringing real-time perfusion imaging for liver, kidney, and the myocardium into reach. New objectives include targeted agents that could further widen USCA applications to specific delivery of active drugs such as anticoagulants or cytotoxic compounds. The combination of new generations of USCAs and new ultrasound image sequences appears to be very promising and currently represents a significant part of ultrasound research.

Ultrasound contrast agents: properties, principles of action, tolerance, and artifacts.

The transforming growth factor (TGF-β) family of growth factors controls an immense number of cellular responses and figures prominently in development and homeostasis of most human tissues. Work over the past decades has revealed significant insight into the TGF-β signal transduction network, such as activation of serine/threonine receptors through ligand binding, activation of SMAD proteins through phosphorylation, regulation of target genes expression in association with DNA-binding partners and regulation of SMAD activity and degradation. Disruption of the TGF-β pathway has been implicated in many human diseases, including solid and hematopoietic tumors. As a potent inhibitor of cell proliferation, TGF-β acts as a tumor suppressor; however in tumor cells, TGF-β looses anti-proliferative response and become an oncogenic factor. This article reviews current understanding of TGF-β signaling and different mechanisms that lead to its impairment in various solid tumors and hematological malignancies.

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TGF-β – an excellent servant but a bad master

This randomized, open-label, active-controlled, dose-finding phase IIb study evaluated the efficacy and safety of trabedersen (AP 12009) administered intratumorally by convection-enhanced delivery compared with standard chemotherapy in patients with recurrent/refractory high-grade glioma. One hundred and forty-five patients with central reference histopathology of recurrent/refractory glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) were randomly assigned to receive trabedersen at doses of 10 or 80 µM or standard chemotherapy (temozolomide or procarbazine/lomustine/vincristine). Primary endpoint was 6-month tumor control rate, and secondary endpoints included response at further timepoints, survival, and safety. Six-month tumor control rates were not significantly different in the entire study population (AA and GBM). Prespecified AA subgroup analysis showed a significant benefit regarding the 14-month tumor control rate for 10 µM trabedersen vs chemotherapy (p= .0032). The 2-year survival rate had a trend for superiority for 10 µM trabedersen vs chemotherapy (p = .10). Median survival for 10 µM trabedersen was 39.1 months compared with 35.2 months for 80 µM trabedersen and 21.7 months for chemotherapy (not significant). In GBM patients, response and survival results were comparable among the 3 arms. Exploratory analysis on GBM patients aged ≤55 years with Karnofsky performance status >80% at baseline indicated a 3-fold survival at 2 and 3 years for 10 µM trabedersen vs chemotherapy. The frequency of patients with related or possibly drug-related adverse events was higher with standard chemotherapy (64%) than with 80 µM trabedersen (43%) and 10 µM trabedersen (27%). Superior efficacy and safety for 10 µM trabedersen over 80 µM trabedersen and chemotherapy and positive risk-benefit assessment suggest it as the optimal dose for further clinical development in high-grade glioma.

http://www.isarna-therapeutics.com/fileadmin/user_upload/documents/publications/Bogdahn_et_all_HGG_Neuro-Oncology_2010.pdf

Targeted therapy for high-grade glioma with the TGF-β2 inhibitor trabedersen: results of a randomized and controlled phase IIb study

Transforming growth factors-beta 1 and -beta 2 (TGF-beta 1 and -beta 2) are important growth-regulatory proteins for astroglial neoplasms. We analyzed their role in tumor-cell proliferation in 12 glioma cell lines, employing phosphorothioate antisense oligodeoxynucleotides (S-ODNs, 14 mer), specifically targeted against the coding sequences of TGF-beta 1-mRNA and TGF-beta 2-mRNA. TGF-beta 1-S-ODNs inhibited cell proliferation in 5 of 12 gliomas, whereas TGF-beta 2-S-ODNs reduced the cell proliferation in all glioma cell lines, compared to nonsense-S-ODN-treated and S-ODN-untreated cells as controls. The efficacy and specificity of antisense effects was validated by Northern-blot analysis and determination of protein concentrations in culture supernatants (ELISA). Exogenous hrTGF-beta 1 either stimulated or inhibited the cell lines, whereas pnTGF-beta 2 stimulated the proliferation of most glioma cells. Blocking the extracellular pathway of TGF-beta by neutralizing antibodies only slightly inhibited those cell lines, which were markedly stimulated by TGF-betas. As the effects of TGF-beta 2-S-ODNs were much stronger than those of TGF-beta neutralizing antibodies, we postulate that the endogenously produced TGF-beta 2 control glioma-cell proliferation, in part by an intracellular loop.

Transforming growth factor-beta-mediated autocrine growth regulation of gliomas as detected with phosphorothioate antisense oligonucleotides.

Transcranial duplex sonography using ultrasound contrast enhancers.

Twelve patients with insufficient transcranial Doppler signal underwent transcranial color-coded ultrasonography before and after administration of SH U 508A with different modes of administration. Clinically useful enhancement time after bolus injection was surpassed by that after standard infusion (1 mL/min), whereas further prolongation was observed after individualized infusion. Intravenous infusion of SH U 508A provides a prolonged useful enhancement compared with that after bolus injection.

Echo-enhanced transcranial color-coded US: clinical usefulness of intravenous infusion versus bolus injection of SH U 508A.

The invention pertains to the use of a pharmaceutical composition containing deuterium and/or deuterated substances and/or substances that enrich or release deuterium to selectively destroy tumor cells and/or tumor metastases or to prevent metastasizing and/or local recurrence of tumors as well as their regrowth.

Deuterium-containing pharmaceutical compositions for destroying tumors

Introduction Transcranial Duplex Sonography (TDS, synonym: transcranial colour coded real time sonography, TCCS) has been further improved: aside from vascular and parenchymal anatomy, a broad spectrum of intracerebral pathology may be disclosed. Transpulmonary stable ultrasound contrast agents further improve image quality and signal intensity, with a broad spectrum of new applications. A synopsis of the applications of galactose-based contrast agents may be found in the review by Schlief et al [Schlief, 1993, #16]. Aside from a complete depiction of the arterial system and the basal veins, candidates for contrast-enhanced transcranial sonography may be mainly lesions with low blood flow velocities. There are advantages over conventional pulsed transcranial sonography (TCD): (1) rapid identification of large intracranial vessels within the B-mode image, resulting in shorter examination times and improved standardisation and reproducibility; (2) real time localisation of vascular pathology by colour imaging within the black and white B-mode image of the parenchyma, and (3) detection of parenchymal lesions with new diagnostic information, complementing MRIand CT-findings [Becker, 1992, #4].

Albrecht Bauer

Papers

Transforming growth factor-beta-mediated autocrine growth regulation of gliomas as detected with phosphorothioate antisense oligonucleotides.

Transcranial duplex sonography using ultrasound contrast enhancers.

Echo-enhanced transcranial color-coded US: clinical usefulness of intravenous infusion versus bolus injection of SH U 508A.

Deuterium-containing pharmaceutical compositions for destroying tumors

Contrast-Enhanced Transcranial Duplex Sonography