Minimally invasive biomarkers for therapy monitoring.
Development of new drugs and optimal application of the drugs currently in use in clinical chemotherapy requires the application of biomarkers. Ideally, these biomarkers would stratify patients so that only those patients likely to respond to a particular therapy receive that therapy. However, that is not always feasible, and an alternative is to make use of early response biomarkers to determine the responding population. In this paper, a number of generic (i.e. not necessarily specific to the action mechanism of the compound) early-response biomarkers are discussed and compared in different models and with three compounds with quite different mechanisms of action: a VEGF-R inhibitor (PTK787), an mTOR inhibitor (RAD001) and a microtubule stabiliser (EPO906). The methods include noninvasive DCE-MRI and PET imaging for measuring tumour vascularity, metabolism and proliferation, as well as the minimally invasive WIN method for measuring tumour interstitial pressure (IFP). The data show that drug-induced changes in IFP (delta IFP) involve mechanism-dependent changes in the tumour vascular architecture, and that delta IFP may be considered a universal generic early-response marker of tumour response to therapy.
McSheehy
P
P
Oncology Research, Novartis Pharma AG, 4002 Basel, Switzerland. paul_mj.mcsheehy@novartis.com
Allegrini
P
P
Ametaby
S
S
Becquet
M
M
Ebenhan
T
T
Honer
M
M
Ferretti
S
S
Lane
H
H
Schubiger
P
P
Schnell
C
C
Stumm
M
M
Wood
J
J
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D045604:Extracellular Fluid / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D049268:Positron-Emission Tomography; D011312:Pressure; D051381:Rats; D011914:Rats, Inbred BN; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor