Bms275291

Synthetic analogue of fumagillin; inhibition of Ets-1

Unknown

Inhibition sodium-hydrogen exchanger, NHE3

Induction of apoptosis in proliferating endothelial cells

Humanized mAb to VEGF

Antibody to VEGFR-2

Inhibition of VEGF

signaling by sequestration of VEGF and possibly formation of inactive heterodimers with cell-surface VEGF receptors

Cleavage of mRNA of VEGFR-1

Small molecule inhibitor of VEGFR-2, PDGFR, KIT and FLT-3

Small molecule blocker of VEGF-receptor, FGF, and PDGF receptor signaling

Inhibition of VEGFR-1,2,3 TKI

Small molecule inhibitor of 0^3 and 0^5

Synthetic inhibitor that blocks TNF—a convertase; inhibitor of MMPs

Synthetic MMP inhibitor

MMP inhibitor and tetracycline derivative

Natural MMP inhibitor; derivative of shark cartilage

Synthetic MMP inhibitor

Phase II advanced cancer, lymphomas and acute leukemia

Phase I malignant glioma & melanoma Phase II non-small cell lung cancer; phase II

in CRC, lymphoma, MDS, liver, CLL, NSCLC Phase III prostate, myeloma, RCC

Phase I solid tumors; phase II non-small cell lung cancer and solid tumors

Phase I solid tumors; phase II to begin in mid-2000

Phase I advanced neuroendocrine and melanoma

Phase I advanced tumors

Phase II metastatic RCC, advanced prostate, NSCLC, colorectal and other solid tumours

Preclinical

Phase I advanced tumors

Phase I/II refractory solid tumors

Phase I advanced solid tumors

Phase I in selected advanced tumors

Phase I/ II with chemotherapy in CRC

Phase I advanced tumors

Phase I pancreatic cancer; phase III NSCLC, small cell lung cancer and breast cancer; phase I GBM

Phase III NSCLC, hormone refractory prostate, pancreatic, and small cell lung cancer

Phase I/II brain, Kaposi's sarcoma

Phase II multiple myeloma, Phase III renal cell cancer, Phase III non-small cell lung cancer

Phase I

Cerebellar dysfunction

Fatigue, somnolence, myelosuppression, peripheral neuropathy, thromboembolism (in combination with chemotherapy)

Rash Erythema

Thrombosis, proteinuria, hypertension

Hypertension, fatigue, proteinuria

Asthenia, thrombocytopenia, neutropenia, skin discoloration, depigmentation

Asthenia, thrombocytopenia, hypertension, diarrhea

Fatigue, neuropathy, diarrhea

Musculoskeletal pain and joint swelling

Lupus, anemia provides maximal target inhibition.114 Because determining target inhibition within the tumor is technically demanding, the sampling of normal or surrogate tissues has been an alternative approach. Examples of surrogate tissue use include the measurement of p70S6 kinase activity in peripheral blood mononuclear cells after treatment with an mTOR inhibitor, the assessment of EGFR and ERK/MEK phosphorylation status in skin biopsies after treatment with EGFR tyrosine kinase inhibitors, or assessment of prelamin A farnesylation in buccal mucosal cells following FTI treatment.42 However, reliance on surrogate endpoints to determine the efficacy of these targeted therapies has attracted criticism because the pharmacodynamics within normal tissue may not reflect target inhibition within the tumor mass. For example, clinical trials investigating the activities of the EGFR inhibitors have failed to adequately assess the intratumoral pharmaco-

dynamics before and after drug exposure.2 Therefore, negative trial data may simply reflect inadequate drug dosage and tumor tissue concentrations of these agents rather than drug inactivity, which raises serious questions over the interpretation of negative clinical trial data unless proof of target inhibition is documented within tumor specimens rather than surrogate tissues.

Noninvasive functional imaging techniques that can quantify the level of target function in vivo are under investigation and include dynamic contrast-enhanced MRI (DCE MRI) for measuring tumor vascularization and vascular permeability with angiogenesis inhibitors and positron emission tomography (PET) to monitor metabolic changes in uptake of 18F-fluoro-2-deoxy-d-glucose (18FDG) within the tumor mass. Other functional modalities include doppler ultrasound and dynamic infrared imaging of vascular perfusion patterns.115

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