Trials probe new agents for kidney cancer.
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Antibodies, Monoclonal↗
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Assessment of anti-metastatic drug efficacy via localization and quantification of ex vivo murine bone tumor load using high-throughput MRI T1 parametric analysis.
MRI methods show great utility for assessing the growth of tumors metastasized to bone in clinical studies. However, preclinical MRI methods in rodents do not translate well to high-throughput studies of bone tumors, especially for early-stage tumors typically examined in pharmaceutical discovery efforts. To overcome these limitations, an ex vivo MR T1 parametric mapping method has been developed to measure metastasized bone tumor load in murine long bones. This method has been used to assess the therapeutic efficacy of SU11248, a multi-targeted inhibitor with demonstrated anti-tumor activity and reduction of bone loss, in a murine model of metastasized breast tumor cells. The results show precise localizations of relative tumor loads within the bones and reveal significant differences between SU11248-treated and untreated animal groups. The procedures were optimized for simultaneous, high-throughput parallel image acquisition of MRI data for 30 samples and included an automated segmentation method for image processing. The merits of this T1 parametric mapping method are compared with clinical T1-weighted MRI methods, histopathology and bioluminescence imaging of the same murine bone tumor model.
Animals↗
[Translational research in renal cell cancer. Illustrated by the example of the vascular endothelial growth factor pathway].
For patients with metastatic renal cell cancer (RCC), therapeutic options after cytokine failure are rather limited. There is a considerable need to identify new substances for systemic therapy. Due to upregulation after the loss of a functional von Hippel Lindau gene product, the vascular endothelial growth factor (VEGF) pathway is a promising target for a molecular based therapy. Over the last few years, therapeutic agents have been developed which inhibit this pathway at various levels. Here, we provide an overview of the molecular background and currently used drugs which have entered clinical trials in the setting of metastatic RCC disease. Until now, the results from early clinical trials are very promising, however, the best schedule, dosage, potential combination regimens, as well as long time efficacy, are still to be determined.
Angiogenesis Inhibitors↗
Molecular targeting therapy for renal cell carcinoma.
Metastatic renal cell carcinoma (RCC) is currently one of the most treatment-resistant malignancies. However, significant advances in understanding the molecular mechanisms underlying RCC have led to the development of rationally designed therapies, which are now being tested clinically. To date, the vascular endothelial growth factor receptor (VEGFR) pathway has been the most promising target, and two agents (BAY 43-9006 and SU 11248) that inhibit not only VEGFR but also other receptors, including platelet-derived growth factor receptor (PDGFR), FMS-like tyrosine kinase 3 (FLT3), KIT, and Raf kinase, were recently approved by the FDA for advanced RCC. In addition, a phase III trial investigating the addition of VEGF inhibition to interferon alpha (IFN-alpha) in RCC is also now going on. Although the clinical activity of existing agents is to be further defined in ongoing trials, the exciting clinical response data with VEGF inhibition in RCC have demonstrated a key role in the treatment of this historically resistant malignancy.
Antibodies, Monoclonal↗
The receptor tyrosine kinase inhibitor SU11248 impedes endothelial cell migration, tubule formation, and blood vessel formation in vivo, but has little effect on existing tumor vessels.
Antiangiogenic agents produce regression in few tumors in clinical trials, but are effective in preventing recurrences. To determine whether the vascular endothelial growth factor (VEGF) receptor is a molecular target to prevent metastatic disease, we utilized a non-specific inhibitor of the VEGF receptor, SU11248. This receptor tyrosine kinase (RTK) inhibitor prevented migration of endothelial cells and markedly attenuated capillary-like tubule formation in endothelial cells in culture. Similarly, this agent prevented blood vessel formation in the tumor vascular window model. VEGF RTK inhibition produced minimal effects on established blood vessels in the tumor vascular window model and little effect on blood flow studied by power Doppler analysis. To determine whether these agents attenuate the development of metastases, Lewis lung carcinoma tumors were resected from the dorsal skin and lung metastases were quantified with and without treatment with SU11248. The RTK inhibitor attenuated the formation of lung metastases following resection of the hind limb tumor. In contrast, these agents did not induce regression of primaries but slowed the progression of tumor growth. These findings suggest that the greatest role for VEGF antagonists may be to prevent the formation of new blood vessels, during and after conventional therapy is given to existing neoplastic disease.
Angiogenesis Inhibitors↗
New therapeutic strategies for soft tissue sarcomas.
The treatment of patients with metastatic soft tissue sarcomas (STS) is complex. There are limited agents available and many are associated with significant toxicity. When evaluating a patient with metastatic disease, physicians should ask themselves whether there is a role for surgery to render the patient free of disease. Combination chemotherapy in patients who have not received chemotherapy in the adjuvant setting is one option, particularly in a young patient with a good performance status. Sequential single-agent therapy for patients who are more elderly or debilitated by their disease may be more appropriate. Gemcitabine appears to be an agent with activity, particularly in patients with leiomyosarcomas. The data regarding prolonged gemcitabine infusions suggest improved activity that was predicted based on prolonged intracellular gemcitabine levels. Because of these data, the prolonged infusion schedule should be used. In addition, because of the paucity of effective agents, consideration of clinical trial participation for patients with newly diagnosed metastatic disease is appropriate, particularly in chemotherapy-insensitive histologies. The role of the newer agents (eg, ecteinascidin-743, epothilones, and mammalian target of rapamycin) is undefined. Ecteinascidin-743 has been the most extensively tested agent, and its ability to slow growth kinetics of a tumor and stabilize it clinically is intriguing. Data regarding the response to BMS-247550 will be published shortly and will help define the further role of epothilones in this disease. There is a preclinical rationale that makes the mammalian target of rapamycin inhibitors attractive for the treatment of muscle-derived neoplasms. In addition, there are cell-line data suggesting activity in rhabdomyosarcoma. These agents are being tested in adult STS and will likely be tested in pediatric histologies when there are more safety data available in that population. SU11248 will continue to be tested in patients refractory to imatinib mesylate and may well prove to be another active agent for patients with gastrointestinal stromal tumors. As depicted by the analysis of gemcitabine efficacy, agents with activity in a subgroup of STS may be overlooked by the "come one come all" approach to clinical trials in STS. Identifying key targets in specific STS will be helpful in the testing of newer molecularly targeted agents. Biologic differences will support histology-specific trials to better understand the activity of an agent in a specific disease site or specifically target a biologic pathway with relevance to the malignant potential of the disease. For future clinical trials in STS to achieve the goal of histology-specific trials, cooperative group and multi-institutional trials will be required to obtain the appropriate patients with these rare histologies. It will also be increasingly important to be committed to obtaining tumor tissue in these patients to validate hypotheses regarding tumor biology and the effectiveness of therapeutic agents.
Antineoplastic Agents↗
Promising systemic therapy for renal cell carcinoma.
In the United States, advanced kidney cancer accounts for over 12,000 deaths each year. Immunotherapy with either interferon or interleukin-2 (IL-2) has been the standard of care for over two decades. High-dose IL-2 can apparently cure 10% to 15% of patients treated, but due to the required inpatient care and the attendant toxicities, it is only administered to less than 1,000 patients per year in the United States (Chiron, personal communication). Interferon is a less active agent than IL-2 but it has still been shown to be superior to therapy with either megesterol or vinblastine. Interferon typically results in very few long-term responses and is given to most patients with metastatic kidney cancer. Median survival after interferon therapy is dependent on risk group but is typically 12 to 15 months. Thus, new therapies are urgently needed in this refractory disease. Novel compounds currently being tested in clinical trials are showing promise in advanced kidney cancer. The molecular targets of these drugs include interfering with the vascular endothelial growth factor receptors or the raf kinase pathway, angiogenesis inhibition, and antimicrotubule agents. A review of the preclinical and early clinical development of some of these novel compounds will be discussed.
Animals↗
Novel kinase inhibitors in renal cell carcinoma: progressive development of static agents.
The rapidly expanding knowledge regarding neoplastic diseases is providing a plethora of new targets for drug discovery and development as exemplified by recent data in renal cell carcinoma. The initial experience with molecularly "targeted" agents has demonstrated that development of the newer non-cytotoxic agents will provide unique challenges requiring modification of many traditional drug development concepts and methods. We discuss recently reported data from a few renal cell carcinoma trials with putative cytostatic agents and highlight issues that need to be addressed for efficient development of cytostatic agents during various phases of clinical development.
Angiogenesis Inhibitors↗
VEGF-targeted therapy in renal cell carcinoma: active drugs and active choices.
Several molecular pathways are implicated in renal cell carcinoma (RCC) pathogenesis, including von Hippel--Lindau (VHL) gene inactivation leading to vascular endothelial growth factor (VEGF) expression. Therapeutic targeting of VEGF and related pathways has been undertaken in metastatic RCC. Substantial clinical activity has been reported for multiple agents, leading to several clinical questions regarding the optimal use of these agents. The biology, clinical results, and future considerations regarding VEGF-targeted agents in RCC are presented in this article.
Angiogenesis Inhibitors↗
Synthesis of [18F]SU11248, a new potential PET tracer for imaging cancer tyrosine kinase.
N-[2-(Diethylamino)ethyl]-5-[(Z)-(5-[18F]fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, a new potential positron emission tomography tracer for imaging cancer tyrosine kinase, has been prepared by the nucleophilic substitution of the nitro-precursor N-[2-(diethylamino)ethyl]-5-[(Z)-(5-nitro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide with K18F/Kryptofix 2.2.2 followed by a simple chromatography methodology combined solid-phase extraction with high-performance liquid chromatography purification procedures in 15-25% radiochemical yields.
Fluorine Radioisotopes↗
Quantitation of SU1 1248, an oral multi-target tyrosine kinase inhibitor, and its metabolite in monkey tissues by liquid chromatograph with tandem mass spectrometry following semi-automated liquid-liquid extraction.
SU11248 is a potent inhibitor of PDGFR, VEGFR, KIT, and Flt3, and is currently under Phase I clinical evaluation as an anticancer drug. A sensitive and specific analytical method for the quantitation of SU11248 and its metabolite in several monkey tissues (liver, kidney, brain and white fat) using LC-MS-MS following semi-automated liquid-liquid extraction (LLE) was developed and validated. Amounts of 50 mg of tissue were homogenized using an ultrasonic processor. After addition of the stable labelled internal standard (IS) and ammonium hydroxide (0.3%), samples were extracted with 2.5 ml of tert-butyl methyl ether. Following centrifugation, aliquots of 1.8 ml of the organic phase were transferred into a 96-well plate. The Packard Multiprobe II robotic liquid handler was used to perform all steps mentioned above. The organic phase was dried and the residue was reconstituted with 800 microl of 15 mM ammonium formate buffer solution (pH 3.25) using a Tomtec Quadra 96 workstation. Aliquots of 10 microl of the resulting solution were injected into the LC-MS-MS system. A Symmetry Shield C8 column (50 mm x 2.1 mm, 3.5 microm) was used to perform the chromatographic analysis. The mobile phase was 15 mM ammonium formate buffer solution (pH 3.25)-acetonitrile (74:26 (v/v)) with a flow-rate of 0.35 ml/min. Retention times of the metabolite and SU11248 were about 2.5 and 3.5 min, respectively. Total cycle time was 5 min. MS detection used the Applied Biosystems-MDS Sciex API 3000 with TurbolonSpray interface and multiple reaction monitoring (MRM) operated in positive ion mode. The method was validated for both compounds over the calibration range of about 2 and 2000 ng/g. The suitability and robustness of the method for in vivo samples were confirmed by analysis of monkey tissues from animals dosed with SU11248.
Animals↗
New cancer therapeutics: target-specific in, cytotoxics out?
The International Conference on Molecular Targets and Therapeutics, jointly sponsored by the American Association for Cancer Research (AACR), National Cancer Institute (NCI) and European Organization for Research and Treatment of Cancer (EORTC), was held in Boston on November 17-21, 2003. It offered updates of the latest developments and emerging trends in anti-cancer research. One of the most exciting areas was the development of molecular target-specific therapeutics that have the potential to maximize therapeutic benefit while minimizing toxicity to normal cells. Signifying the coming of age of tumour-specific targets and agents was the recurring theme, to urgently develop and validate biomarker assays as surrogate endpoints; both for showing that targeted agents act as expected and for providing proof of concept in the scientific rationale of new agents. Given the dominance of protein tyrosine kinase inhibitors in small-molecule drug design, a strong case was made for the implementation of phospho-proteomics or signal transduction signatures and pharmaco-proteomics or chemotherapeutic scans in phase I/II trials--or for the future "Nanolab", eloquently described by Leroy Hood. However, molecular targeted agents-other than imanitib (Gleevec)--have yet to enter broad clinical use and several presentations described efforts for improving classical (cytotoxic) chemotherapeutic agents by targeting them selectively to tumour cells.
Antineoplastic Agents↗
Anti-vascular tumor therapy: recent advances, pitfalls and clinical perspectives.
Anti-vascular tumor therapy represents a promising new strategy for cancer treatment. Anti-vascular treatment may be divided in anti-angiogenic and vascular targeting therapy. Whereas anti-angiogenic drugs aim on the inhibition of new vessel formation, vascular targeting compounds are designed to selectively destruct preexisting tumor blood vessels leading to secondary tumor cell death. Both anti-angiogenic drugs and vascular targeting agents have proven effective anti-tumoral activity in numerous preclinical studies over the last decade. In vivo, a combination with anti-vascular tumor therapy enhances the effects of other treatment modalities as chemo- and radiotherapy. Phase I clinical studies revealed a number of well-tolerated candidates. As monotherapy, however, anti-angiogenic treatment lacked efficacy in randomized clinical studies so far. In contrast, combination of anti-angiogenic therapy with chemotherapy was highly effective in an encouraging, large randomized phase III trial on metastatic colorectal cancer. This review will outline recent advances in the preclinical and clinical development of anti-vascular therapy with focus on vascular targeting. Conceptual differences between anti-angiogenic and vascular targeting therapies will be discussed with emphasis on specific problems and pitfalls in the conversion into the clinic.
Animals↗
Molecular strategies targeting the host component of cancer to enhance tumor response to radiation therapy.
The tumor microenvironment, in particular, the tumor vasculature, as an important target for the cytotoxic effects of radiation therapy is an established paradigm for cancer therapy. We review the evidence that the phosphoinositide 3-kinase (PI3K)/Akt pathway is activated in endothelial cells exposed to ionizing radiation (IR) and is a molecular target for the development of novel radiation sensitizing agents. On the basis of this premise, several promising preclinical studies that targeted the inhibition of the PI3K/Akt activation as a potential method of sensitizing the tumor vasculature to the cytotoxic effects of IR have been conducted. An innovative strategy to guide cytotoxic therapy in tumors treated with radiation and PI3K/Akt inhibitors is presented. The evidence supports a need for further investigation of combined-modality therapy that involves radiation therapy and inhibitors of PI3K/Akt pathway as a promising strategy for improving the treatment of patients with cancer.
Angiogenesis Inhibitors↗
New drug increases survival in stomach cancer.
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Gastrointestinal Stromal Tumors↗
Early clinical data with small-molecule vascular endothelial growth factor tyrosine kinase receptor inhibitors.
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Angiogenesis Inhibitors↗
Discovery of 5-[5-fluoro-2-oxo-1,2- dihydroindol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase.
To improve the antitumor properties and optimize the pharmaceutical properties including solubility and protein binding of indolin-2-ones, a number of different basic and weakly basic analogues were designed and synthesized. 5-[5-Fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (12b or SU11248) has been found to show the best overall profile in terms of potency for the VEGF-R2 and PDGF-Rbeta tyrosine kinase at biochemical and cellular levels, solubility, protein binding, and bioavailability. 12b is currently in phase I clinical trials for the treatment of cancers.
3T3 Cells↗
SU11248 inhibits tumor growth and CSF-1R-dependent osteolysis in an experimental breast cancer bone metastasis model.
The aim of the study was to investigate inhibitory effects of the receptor tyrosine kinase (RTK) inhibitor SU11248 against CSF-1R and osteoclast (OC) formation. We developed an in vivo model of breast cancer metastasis to evaluate efficacy of SU11248 against tumor growth and tumor-induced osteolysis in bone. The in vitro effects of SU11248 on CSF-1R phosphorylation, OC formation and function were evaluated. Effects on 435/HAL-Luc tumor growth in bone were monitored by in vivo bioluminescence imaging (BLI), and inhibition of osteolysis was evaluated by measurement of serum pyridinoline (PYD) concentration and histology. Phosphorylation of the receptor for M-CSF (CSF-1R) expressed by NIH3T3 cells was inhibited by SU11248 with an IC50 of 50-100 nM, consistent with CSF-1R belonging to the class III split kinase domain RTK family. The early M-CSF-dependent phase of in vitro murine OC development and function were inhibited by SU11248 at 10-100 nM. In vivo inhibition of osteolysis was confirmed by significant lowering of serum PYD levels following SU11248 treatment of tumor-bearing mice (P = 0.047). Using BLI, SU11248 treatment at 40 mg/kg/day for 21 days showed 64% inhibition of tumor growth in bone (P = 0.006), and at 80 mg/kg/day showed 89% inhibition (P = 0.001). Collectively, these data suggest that SU11248 may be an effective and tolerated therapy to inhibit growth of breast cancer bone metastases, with the additional advantage of inhibiting tumor-associated osteolysis.
Animals↗