Drug Discovery by Molecular Imaging and Monitoring Therapy Response in Lymphoma

Abstract So far, data based on small patient (pt) population suggest that the measurement of serum FLC from MM pts undergoing high-dose chemotherapy (HDCT) with stem cell transplantation (SCT) may be a sensitive marker for monitoring therapy success and for early detection of relapse. For further evaluation of the impact of FLCs on the assessment of treatment efficacy of standard- (ST) and HDCT with SCT, we performed a prospective analysis on serial serum specimens from 86 MM and 9 control pts. Measurement of FLC concentration was performed with the commercially available Freelite™ kit (Binding Site). For statistical analysis, pts’ clinical history, age at diagnosis, sex, current state of disease, karyotype and serum parameters, such as ß2-microglobulin, calcium levels and serum creatinine were evaluated. In the control group (NHL=6, AML=1, non-hematological disease=2), median concentrations of kappa(k)- and lambda(l)- FLC were 9.8 mg/l and 12.8 mg/l, respectively, corresponding to reference intervals for healthy individuals with normal kappa(k)/lambda(l)-ratios. In MM, 40 (46.5%) pts displayed kappa(k)-FLC levels above the upper range of 19mg/l, 26 (30%) had lambda(l)-FLC levels above the upper range of 26 mg/l and 9 pts (10.4%) had both elevated kappa(k)- and lambda(l)-FLC serum levels. An abnormal kappa(k)/lambda(l)-ratio was observed in 45 (52,3%) MM pts. Pts with a known kappa(k)-paraprotein (n=58) had a median FLC kappa(k)-concentration of 38 mg/l, but lambda(l)-FLC within the normal range. For pts with a known lambda(l)-paraprotein (n=27), reciprocal findings (76.4 mg/l for lambda(l)- vs kappa(k)-FLC in the normal range) were observed. Pts with responsive disease (CR, PR and SD) had both kappa(k)- and lambda(l)- FLC levels within the normal range, whereas newly diagnosed pts (ED) and those with PD had kappa(k)- FLC levels approx. 3-times the normal range, with lambda(l)- FLC levels at the upper limit of normal. Pts receiving ST as compared with HDCT had higher FLC levels. This is also observed in pts with amyloidosis, renal impairment or PD. Our results suggest that serum FLC assay allows monitoring of the therapy response and early detection of relapse. Determination of FLCs is also important, when evaluating new therapeutic substances, and for detection of prognostic patterns for better risk-based stratification of treatment.

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Nuclear molecular imaging: a novel means of drug discovery in gene therapy?

Drugs of the Future ◽

10.1358/dof.2005.030.03.886980 ◽

2005 ◽

Vol 30 (3) ◽

pp. 311 ◽

Cited By ~ 2

Author(s):

E.K.J. Pauwels

Keyword(s):

Gene Therapy ◽

Drug Discovery ◽

Molecular Imaging

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Molecular Imaging for Acceleration of Drug Discovery & Development and Innovation of Clinical Diagnosis and Therapy

YAKUGAKU ZASSHI ◽

10.1248/yakushi.129.263 ◽

2009 ◽

Vol 129 (3) ◽

pp. 263-264

Author(s):

Hideo SAJI ◽

Kazuya KIKUCHI

Keyword(s):

Drug Discovery ◽

Molecular Imaging ◽

Clinical Diagnosis ◽

Diagnosis And Therapy

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Near-infrared fluorescence molecular imaging of amyloid beta species and monitoring therapy in animal models of Alzheimer’s disease

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1505420112 ◽

2015 ◽

Vol 112 (31) ◽

pp. 9734-9739 ◽

Cited By ~ 99

Author(s):

Xueli Zhang ◽

Yanli Tian ◽

Can Zhang ◽

Xiaoyu Tian ◽

Alana W. Ross ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Imaging ◽

Amyloid Beta ◽

Near Infrared ◽

Imaging Data ◽

Curcumin Analog ◽

Near Infrared Fluorescence ◽

Brain Extraction ◽

Monitoring Therapy

Near-infrared fluorescence (NIRF) molecular imaging has been widely applied to monitoring therapy of cancer and other diseases in preclinical studies; however, this technology has not been applied successfully to monitoring therapy for Alzheimer’s disease (AD). Although several NIRF probes for detecting amyloid beta (Aβ) species of AD have been reported, none of these probes has been used to monitor changes of Aβs during therapy. In this article, we demonstrated that CRANAD-3, a curcumin analog, is capable of detecting both soluble and insoluble Aβ species. In vivo imaging showed that the NIRF signal of CRANAD-3 from 4-mo-old transgenic AD (APP/PS1) mice was 2.29-fold higher than that from age-matched wild-type mice, indicating that CRANAD-3 is capable of detecting early molecular pathology. To verify the feasibility of CRANAD-3 for monitoring therapy, we first used the fast Aβ-lowering drug LY2811376, a well-characterized beta-amyloid cleaving enzyme-1 inhibitor, to treat APP/PS1 mice. Imaging data suggested that CRANAD-3 could monitor the decrease in Aβs after drug treatment. To validate the imaging capacity of CRANAD-3 further, we used it to monitor the therapeutic effect of CRANAD-17, a curcumin analog for inhibition of Aβ cross-linking. The imaging data indicated that the fluorescence signal in the CRANAD-17–treated group was significantly lower than that in the control group, and the result correlated with ELISA analysis of brain extraction and Aβ plaque counting. It was the first time, to our knowledge, that NIRF was used to monitor AD therapy, and we believe that our imaging technology has the potential to have a high impact on AD drug development.

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