Sunday, April 5, 2015
Currently, [18F]fluorodeoxyglucose, or 18FDG, is the only PET radiopharmaceutical for tumor imaging in wide clinical use, and it is a tool with which oncologists are familiar. However, it is of limited value in certain organ systems and types of cancers, including pancreatic and gastric. Memorial Sloan Kettering Cancer Center (MSK) researchers are developing new radiotracers for clinical PET imaging, including radiotracers that are fundamentally new to Radiology – beyond those that have been used traditionally in tumor detection, staging, and response evaluation. Ongoing first-in-human trials at MSK already demonstrate the clinical feasibility of tumor imaging with these novel tracers. These emerging pharmacometric radiotracing agents show promise to revolutionize both oncologic imaging and development of targeted pharmacotherapeutics.
The recent explosion in genetic information has led to the discovery of genes and cellular pathways that are involved in the development and progression of cancer. Consequently, targeted imaging for targeted therapy is advocated by the National Cancer Institute and others (1) for advancement of medical imaging and drug development. Collaboration with imaging scientists early in the drug development process is also encouraged.
For example, information gleaned from early pharmacometric studies using PET-based tracers can guide refinements in tumor type selection and drug design. Pharmacometric PET tracers can be broadly classified as in vivo clinical assays of tumor biomolecular pharmacotherapeutic targets or associated biomarkers, and as radiolabeled versions of novel anti-cancer drugs for imaging assay of tumor pharmacokinetics.
Although tumor response to anti-cancer drugs is usually dose-dependent, resistance to targeted drugs can be mediated by in vivo mechanisms that reduce tumor dose. MSK clinical radiology researchers are designing radiotracers of therapeutic agents to evaluate the in vivo bioavailability of tumor targets in an individual patient. Thus, one can provide a pre-treatment snapshot of available targets for the therapy being considered.
In addition, researchers are developing methods for in vivo visualization of intratumoral concentrations of radiolabeled versions of novel drugs across time to guide the selection of dose and schedule. Such pharmacometric assays are needed because serial tumor biopsies are invasive and potentially non-representative of an individual’s metastatic disease overall, and because current non-invasive plasma pharmacokinetic methods fail to predict tumor concentrations of certain drugs. (2)Back to top
Fluoroglutamine PET and CB-839
As noted, FDG-PET has limited utility in certain cancers, such as pancreatic and gastric malignancies. One alternative to FDG currently being evaluated by MSK researchers is [18F]4-L-fluoroglutamine (2S,4R), or fluoroglutamine, a glutamine analog. (3) Fluoroglutamine PET can provide an investigational clinical imaging biomarker to evaluate in vivo tumor uptake of exogenous glutamine (Figure 1).
Also, preclinical validation demonstrates that pharmacotherapeutic targeting of the glutamine metabolic pathway has anti-tumor activity in cells “addicted” to the uptake of exogenous glutamine as a substrate. (4) It is notable that this pathway is dispensable in normal cells. Interestingly, human pancreatic ductal adenocarcinoma cells (KRAS oncogene) require glutamine for tumor growth. (5)
With support from Stand Up To Cancer® (su2c.org), fluoroglutamine PET is now in its first clinical trial (IRB#12-168) at MSK. In parallel, our researchers recently opened two phase 1 clinical trials testing CB-839, a first-in-class small molecule inhibitor of glutaminase, as an investigational therapeutic for solid tumors or hematologic malignancies including hepatopancreatobiliary (IRB#14-111; IRB#14-053). Patients from the CB-839 therapeutic trials are welcome in the fluoroglutamine imaging trial. Thus, fluoroglutamine PET has potential applications not only in development of this new class of pharmacotherapeutics, but also as an alternative to FDG in imaging certain organ systems and cancers.Back to top
Dasatinib and 18F-SKI-249380
Pharmacometrics are crucial for the continued development of novel drugs that are effective in only a subset of patients. (6) One such promising pharmacotherapeutic is dasatinib, the prototypical Src/Abl inhibitor. Early-phase clinical trials demonstrate that dasatinib can induce responses in solid malignancies that resist standard therapy, including the most common and most lethal types of cancer. (7) Responses occur in a minority of patients, but these patients showed benefit after standard therapies had failed. Because the responses occur in the most prevalent solid cancers, the number of patients worldwide who can benefit from dasatinib might approach one million annually. The threat facing such promising targeted anti-cancer drugs is that without pharmacometrics, clinical development will end in early phase due to the costs and toxicity associated with non-responsive patients. This comes at the expense of those who would have benefitted.
At MSK, an ongoing clinical trial (IRB#12-182) already shows the clinical feasibility of tumor imaging with 18F-SKI-249380, a radiolabeled dasatinib derivative (Figure 2). (8) Patients from parallel therapeutic trials of dasatinib, including those with hepatopancreatobiliary malignancies, are welcome in this imaging trial.
PU-H71 and 124I-PU-H71
PU-H71 is a very promising, next-generation Hsp inhibitor developed at MSK in collaboration with the National Cancer Institute. Proteomic research has shown that multiple oncoproteins involved in tumor proliferation, survival, and invasive potential are in complex with PU-H71-bound Hsp90 in triple-negative breast cancers.2 The same model shows that PU-H71 can induce complete response without toxicity to the host.
Parallel trials are ongoing at MSK to evaluate PU-H71 and its radiolabeled tracer. The pilot PET imaging study of 124I-PU-H71 (IRB#10-139) was designed to provide data of immediate value (e.g., pharmacokinetic) to investigators for the first-in-human phase 1 trial of PU-H71 in patients with advanced malignancies (IRB#11-041). Patients from the therapeutic trial, including those with hepatopancreatobiliary malignancies, are welcome in the imaging trial. Results already demonstrate the clinical feasibility of Hsp90-targeted PET imaging with 124I-PU-H71. (9)Back to top
On the Horizon
MSK researchers are currently investigating new PET tracers for a wide spectrum of theranostic targets and associated biomarkers, e.g., gastrin-releasing peptide receptor (IRB#14-146); estrogen receptor (IRB#13-071); HER2 (IRB#13-165); androgen receptor (IRB#00-095); PSMA (IRB#13-141; IRB#11-126); STEAP-1 (IRB#12-178); 3F8 (IRB#13-147); carbonic anhydrase-IX (IRB#11-134); BRAF (IRB#14-031); and tumor hypoxia (IRB#10-122; IRB#13-186).
The clinical development of novel targeted pharmacotherapeutics depends heavily upon advances in clinical radiology—advances that will help to answer the question of whether or not an investigational treatment will be effective. The goal of PET researchers at MSK is to improve our ability to answer that question before treatment begins.Back to top