Metastatic Triple negative breast cancer and ovarian cancer are lethal diseases that currently lack effective treatments. Recently developed nanoparticulate forms of active drugs, encapsulated in lipid and polymeric agents, have led to a platform known as nanobins. The lead agents provide dramatically increased efficacy and safety of validated chemotherapeutic agents. The proven ability of these nanobins to safely deliver potent, front line anticancer drugs, such as arsenic trioxide, to tumors with greater efficacy than the parent drugs results in a significantly higher therapeutic index. The established efficacy of this nanotechnology platform arises from both passive, EPR-based and epitope-based molecular targeting strategies. An interdisciplinary team of chemists, tumor biologists, materials scientists, gynecological oncologists, and translational scientists will advance the lead agents to the clinic. In parallel, they will develop new nanobin agents that combine other potent anticancer drugs, such as Cisplatin, with surface tethered antibodies that target tumor specific epitopes. The proposed agents will be also able to deliver multiple sensitizing and cytotoxic agents to solid tumors. The agents will be screened in an experimental matrix that includes quantitative milestones and evaluation of nanobins in several orthotopic xenograph animal models of breast and ovarian cancer. This interdisciplinary team will continue to collaborate with members of the NCI Alliance for Nanotechnology in Cancer to evaluate emerging platforms from other institutions in these animal models of rare gynecological and metastatic breast cancers. The research efforts of this Platform Partnership will be further augmented and coordinated by a team member with expertise in advancing drugs from the discovery stage to IND filings and to proof of concept phase 2 trials The anticipated outcome of these studies will be the development of safe and effective nanomaterials for the treatment of these currently incurable cancers.

Public Health Relevance

Cancer continues to represent a significant health challenge to the well being of millions of people. Broadly innovative non-traditional therapeutic interventions for the treatment of cancer need to be developed in order to accelerate progress. This application will lead to clinically useful anti-cancer drug candidates and a translational pipeline of nanoparticle based drugs. These agents represent a new paradigm in drug delivery for the treatment of rare and difficult to treat cancers such as ovarian and metastatic breast cancer

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA151461-04
Application #
8536734
Study Section
Special Emphasis Panel (ZCA1-SRLB-X (M1))
Program Officer
Farrell, Dorothy F
Project Start
2010-09-17
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$406,358
Indirect Cost
$103,720
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Beauchamp, Elspeth M; Kosciuczuk, Ewa M; Serrano, Ruth et al. (2015) Direct binding of arsenic trioxide to AMPK and generation of inhibitory effects on acute myeloid leukemia precursors. Mol Cancer Ther 14:202-12
Malin, Dmitry; Strekalova, Elena; Petrovic, Vladimir et al. (2014) *B-crystallin: a novel regulator of breast cancer metastasis to the brain. Clin Cancer Res 20:56-67
Xu, Xiang; Cai, Yuan; Wei, Ying et al. (2014) Identification of a new epitope in uPAR as a target for the cancer therapeutic monoclonal antibody ATN-658, a structural homolog of the uPAR binding integrin CD11b (?M). PLoS One 9:e85349
O'Halloran, Thomas V; Ahn, Richard; Hankins, Patrick et al. (2013) The many spaces of uPAR: delivery of theranostic agents and nanobins to multiple tumor compartments through a single target. Theranostics 3:496-506
Zhang, Yilin; Kenny, Hilary A; Swindell, Elden P et al. (2013) Urokinase plasminogen activator system-targeted delivery of nanobins as a novel ovarian cancer therapy. Mol Cancer Ther 12:2628-39
Ahn, Richard W; Barrett, Susan L; Raja, Meera R et al. (2013) Nano-encapsulation of arsenic trioxide enhances efficacy against murine lymphoma model while minimizing its impact on ovarian reserve in vitro and in vivo. PLoS One 8:e58491
Lee, Kristy; Briehl, Margaret M; Mazar, Andrew P et al. (2013) The copper chelator ATN-224 induces peroxynitrite-dependent cell death in hematological malignancies. Free Radic Biol Med 60:157-67
Swindell, Elden P; Hankins, Patrick L; Chen, Haimei et al. (2013) Anticancer activity of small-molecule and nanoparticulate arsenic(III) complexes. Inorg Chem 52:12292-304
Miodragovic, Ethenana U; Quentzel, Jeremy A; Kurutz, Josh W et al. (2013) Robust Structure and Reactivity of Aqueous Arsenous Acid-Platinum(II) Anticancer Complexes. Angew Chem Int Ed Engl :
Lee, Sang-Min; Lee, One-Sun; O'Halloran, Thomas V et al. (2011) Triggered release of pharmacophores from [Ni(HAsO?)]-loaded polymer-caged nanobin enhances pro-apoptotic activity: a combined experimental and theoretical study. ACS Nano 5:3961-9

Showing the most recent 10 out of 11 publications