AML is a very aggressive blood malignancy with the high mortality (5-year survival rate is less than 40%) and high relapse rate. Additionally, the diversity of AML having 8 subtypes (M0 to M7) presents a challenge for targeted drug development. Currently, therapeutic targets under development focuses on mutated forms of FLT3, RAS and JAK2 (in about 1/3 of AML patients). An anti-CD33 mAb (limited in myeloblast type of AML) conjugated to the antitumor antibiotic calicheamicin was found to improve the survival in a subset of AML patients when combined with standard chemotherapy. However, these anti-AML interventions remain either in the preclinical phase or under clinical trials. Thus, a more effective and alternative pan-AML therapeutic agent will be in great demand. From others and our preliminary work, two AML and leukemia specific markers have been identified. First, CD163, which is a hemoglobin scavenger receptor functioning in mediating endocytic clearance of hemoglobin-haptoglobin (Hb-Hp) complex, has been identified as myeloblastic-monocytic lineage specific. Thus, CD163 represents a potential pan-targeting strategy covering 95% of AML patients. Another candidate, CEACAM6, a cancer-specific carcinoembryonic antigen-related cell adhesion molecule 6, is detected in most leukemia clinical samples and solid tumors such as colorectal, pancreatic and breast cancers. We have developed several anti-CEACAM6 antibodies with both targeting and therapeutic applications. Multifunctional nanoparticles has attracted much interest in the pharmaceutical industries due to their numerous potential applications. Therefore, the development of a multifunctional nanovehicle with the capabilities of targeting AML specifically, real-time monitoring, flexibility of payload drugs and controlled release mechanism is the goal of this program project. It is estimated that AML sales revenue is to reach $324.4 and $106.3 million in the USA and 5EU countries, respectively, reflecting an increased clinical demand. Importantly, our CD163/CEACAM6 bi-specific nanovehicle could also be extended to target multiple cancer types making our system extremely versatile and market-competitive (entering the 10 billion-dollar cancer drug market). In this program project, we have gathered a special team. Uniquely, our PIs (subprojects 1 and 2) are experts in developing multifunctional nanovehicle; PI from subproject 3 focuses on leukemia stem cell biology and xenograft models for preclinical evaluation the nanovehicles. Most importantly, our project leader (subproject 4) is a hemato-oncologist who also has extensive experience in nanomedicine and conducting clinical trials. We believe that under his leadership and the collaborations among co-PIs, our team will strive to translate our research into clinical settings.
|Effective start/end date||8/1/15 → 7/31/16|