Janet F. Eary

The use of radiolabeled antibodies in bone marrow transplantation for hematologic malignancies.

Blood stem cell transplantation has been widely used in the treatment of leukemia and lymphoma for more than two decades. The majority of bone marrow transplant preparative regimens have incorporated total body irradiation (TBI) because lymphohematopoietic cells and their malignant derivatives are relatively radiosensitive. Such preparative regimens have cured a substantial proportion of patients with both acute and chronic leukemia as well as lymphoma. However, despite the radiation sensitivity of hematologic malignancies, relapse remains a major cause of failure.

Radiolabeled antibody therapy of lymphoma

Impressive improvements have occurred over the past 20 years in the development of curative therapies for patients with newly presenting intermediate and high grade lymphomas, as documented in the preceding chapters. However, patients with low grade lymphomas or relapsed non-Hodgin’s lymphomas of any grade are rarely cured with conventional doses of chemotherapy and radiation therapy. High-dose chemoradiotherapy in conjunction with bone marrow transplantation is capable of producing long-term disease-free survival in 20–50% of such patients [1, 2] but is associated with a 10–15% chance of treatment-related mortality. Development of novel new treatment approaches with higher cure rates and less toxicity, therefore, remains a high priority in the field of oncology.

Abstract SY42-02: Novel PET imaging in the clinic: Selecting patient cohorts and measuring early response

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, ILnnMolecular imaging with PET is most commonly associated with tumor detection and staging, currently with [F-18]-fluorodeoxyglucose (FDG-PET) to measure energy metabolism. However other imaging agents can be used to measure important characteristics of tumors that have the potential to guide in therapy selection or provide an early indication of response to therapy. Even though there are enthusiastic predictions of the role that “omics” biomarkers will play in personalized medicine, imaging biomarkers have some practical advantages over tissue and serum biomarkers. Imaging characterizes the entire tumor burden in the context of its environment and it can be repeated frequently. Several new PET agents are becoming widely available to probe important aspects of the tumor phenotype. The UW NCI-sponsored program project is developing PET to image tumor cancer biology with new agents that examine the tumor phenotype and how it changes in response to therapy.nnThere are many biological factors that can influence response of an individual patient to cancer therapy. Evaluation of these factors provides the questions and hypotheses posed in the UW PPG. The group focuses on investigations of reasons for poor tumor response to treatment. Hypoxia, cellular proliferation, low abundance of therapeutic targets (e.g. estrogen receptors) and acquired multidrug resistance (MDR/P-gp) are some of the imaging targets. These tumor variables can be quantified by PET imaging with [F-18]-fluoromisonidazole, [F-18]-3′-fluoro-3′-deoxythymidine, [F-18]-16α-fluoroestradiol and [C-11]-verapamil, respectively. Because hypoxia is a common characteristic of tumors but it is heterogeneous within a tumor mass and differs between tumor sites in a patient, imaging has an important role in assessing regional tumor tissue oxygenation. [F-18]-Fluoromisonidazole (FMISO) developed by our group is a PET hypoxia-imaging probe that accumulates at low PO2. Imaging results with this agent have demonstrated tumor hypoxic volume is an independent predictor of overall survival in patients with head and neck cancer, soft tissue sarcoma and primary brain tumors.nnPET can also be used to image the response mechanism of a tumor to therapy. Current therapies are cytotoxic or cytostatic, with some combinations that are overlapping or aimed at a particular phosphokinase pathway. Uncontrolled tumor growth results from dysregulation of cellular proliferation and/or deficiencies in programmed cell death. FDG has been advocated for monitoring this net process but there are many contributors to energy metabolism in tumors, thus reducing the specificity of FDG-PET for evaluating tumor response. Thymidine and its analogs can be used to image the salvage pathway of cellular proliferation (DNA synthesis) with better specificity because these nucleosides are accumulated and phosphorylated during cellular S-phase. The UW PET group developed [F-18]-3′-fluoro-3′-deoxythymidine (FLT) for this purpose.nnOur recent studies have focused on the challenge of distinguishing whether clinical symptoms and standard imaging appearance after therapy is predominantly a result of tumor progression or radionecrosis/pseudoprogression in patients with primary brain tumors. This application of FLT-PET emphasizes the value of dynamic imaging to separate the blood flow or delivery phase of the imaging agent from its tumor incorporation as a flux through the DNA salvage pathway. Segmentation algorithms and compartmental analyses are being used to generate parametric maps of regional tumor transport and synthetic flux. In several study results, the flux parametric image in recurrent brain tumors shows much higher FLT accumulation (salvage pathway activity) than in tumors with pseudo-progression whereas the transport images overlap between the two groups.nnImaging the P-gp drug resistance mechanism is performed using [C-11]-verapamil, a substrate for the transporter similar to the anthracyclines, which are the mainstay of many chemotherapy regimens. Preliminary work in sarcoma patients has shown that levels of P-gp activity are variable in tumors at presentation and change in response to therapy, usually resulting in an increase in activity. This increase in P-gp activity may confirm clinical suspicion that drug resistance has been induced in an individual as an important contributor to treatment resistance.nnIn summary, PET imaging provides an important tool for selecting patients with specific mechanisms of resistance to cancer therapy so that new drugs can be used with maximum effectiveness. PET imaging results can also provide useful biomarkers for tumor response to standard and experimental therapy, and will be important contributors towards the goal of personalized medicine for cancer patients. The UW PET group has worked with NCI-CIP to develop INDs for FMISO and FLT that are now used in multicenter trials. The group has also developed methods for analysis of FMISO and FLT images and provides a resource for image analysis in the trials. Both of these imaging agents, and approaches to acquiring and analyzing their images, are widely available to nuclear medicine clinical research groups to contribute toward progress in understanding cancer and its response to therapy.nnThe research results to be presented were supported by P01 CA042045-22.nnCitation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY42-02. doi:1538-7445.AM2012-SY42-02

Abstract A230: Exploring novel PET agents for support of experimental cancer therapy: Selecting patient cohorts and monitoring response to therapy

The time course of biodistribution of PET radiopharmaceuticals, when analyzed by appropriate models, can be used to image molecular differences between tumors and normal tissues. Understanding important molecular differences and how they change during treatment should lead to better characterization of tumor biology and ultimately better treatment outcome. Four examples will show the value of PET to image specific aspects of the tumor phenotype. Proliferation imaging started with [C‐11]‐thymidine and later with our development of [F‐18]‐FLT. The salvage pathway provides a robust measure of the growth rate of tumors. As an example, standard therapy for newly diagnosed glioblastoma multiforme is 60 Gy RT plus concurrent temozolomide. Many patients who complete therapy show MRIs consistent with tumor progression but they improve on continued TMZ. This pseudoprogression is an important problem; clinicians armed with MRI alone may wrongly conclude that standard treatment is failing. Misdiagnosing tumor progression could risk entering patients into trials of new agents, leading to falsely positive outcomes. FLT PET may help clarify this dilemma since preliminary studies have shown promise in distinguishing radionecrosis from recurrent disease. In these studies, we assessed FLT flux and transport as well as SUV and MRI and found that only FLT flux was an independent variable to distinguish the two groups. Anthracycline based therapy continues to be a mainstay for solid cancers but many of these tumors have variable levels of multiple drug resistance. Pglycoprotein is a membrane pump to exclude anthracyclines from intracellular accumulation. We use PET to quantify Pgp activity using a transporter substrate, [C‐11]‐verapamil. Pilot studies of sarcoma patients showed a range of uptake kinetics in tumors before treatment compared with after exposure to chemotherapy. Our initial data shows that the extent of acquired MDR measured by PET correlates with survival. Hypoxia is an important resistance factor in treatment. [F‐18]‐FMISO is an imaging agent that accumulates in hypoxia but not in necrosis. In outcomes studies of patients with brain tumors, FMISO was an independent predictor of outcome. Glioma patients with hypoxic volumes >15 cc had a median survival of ∼4 mo while patients with less hypoxia had a median survival of ∼15 mo compared to 12–14 mo with current standard therapy. These data argue that better treatments directed at hypoxic disease deserve serious attention. We have also imaged recurrent malignant gliomas before and after treatment with bevacizumab plus irinotecan and correlated FMISO changes with survival. Our preliminary results argue that anti‐angiogenic therapy may reduce hypoxia and lower resistance to radiotherapy and chemotherapy. We are imaging estrogen receptors using [F‐18]‐fluoroestradiol to select breast cancer patients for targeted therapy. FES predicts response to endocrine therapy in metastatic breast cancer. It shows a pharmacodynamic difference between two ER blocking agents, tamoxifen and fulvestrant. We are beginning to explore the value of FES PET in novel therapy intended to re‐express ER in breast cancer tumors refractory to endocrine therapy using a HDAC inhibitor. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A230.