The Ljubimova Laboratory is working to create a new generation of nanomedicine imaging agents and nanodrugs to bring them to clinical practice. The nanodrugs are biodegradable and nontoxic for patients and deliver multiple antitumor inhibitors, at the same time, directly to cancer cells, overcoming drug resistance and improving treatment efficacy and the quality of cancer patients' lives.
Drugs engineered and tested in the Ljubimova Laboratory offer numerous potential advantages in the fight against deadly cancers. These drugs:
- Are specifically delivered, crossing multiple biological barriers such as the blood-brain barrier and the cancer cell and endosomal membranes
- Have a potential of improving anti-cancer immunotherapy by delivering immune system modifiers directly to tumors
- Release tumor-growth inhibiting agents into cancer cells without affecting normal surrounding cells
- Are backed by preclinical data showing a significant survival increase after being administered to tumor-bearing animals with brain, breast and metastatic cancers
- Make it possible to block a combination of several unique markers for each patient at the same time, providing a synergistic effect
Furthermore, the engineered drugs will be useful for each cancer patient, with adjustments for individual tumor genome/proteome profiles for treatment of primary tumors and for tumor recurrences.
Researchers in the Ljubimova Lab are focusing on brain primary and secondary (brain metastases) cancers — including brain gliomas, which have a very poor prognosis — and HER2-positive and triple negative breast cancers that are largely incurable with current therapy. Other targets include lung cancers and brain metastasis from tumors of the lung, breast and other organs. Compared with chemotherapy, the new nanodrugs from the Polycefin family developed at Cedars-Sinai’s Nanomedicine Research Center are more effective for treating primary and metastatic tumors, increase the maximum useable dose, decrease toxicity and immunogenicity, and enhance our ability to target cancer cells specifically. Using the tumor-targeted delivery method allows anti-cancer agents to accumulate directly in solid tumors, which can aid in fighting multi-drug-resistant cells.
Summary of Nanodrugs and Nanoimaging Agents
Nanobioconjugates were engineered on a natural biodegradable nanoplatform. The drug/imaging agents are specifically delivered crossing multiple bio-barriers such as the blood-brain barrier and the cancer cell membrane to deliver the anti-cancer drugs to the cytoplasm/nuclei of the tumor cells using a targeting monoclonal antibody or peptides. This controllable unique drug releases tumor growth inhibiting agents specifically into cancer cells without affecting normal surrounding cells. Minimal toxicity was demonstrated for nanodrug tumor delivery for temozolomide, platinum drugs and doxorubicin.
MRI virtual biopsy for brain lesions is used when it is impossible to obtain brain tissue for diagnosis
Fig. 1. Multifunctional imaging and treatment agents have been designed to cross BBB through receptor-mediated transcytosis and to deliver drugs to brain cells efficiently and safely. Source: Patil et al, ACS Nano. 2015.
Cross-talk between CK2 and EGFR/EGFRvIII pathways
Fig. 2. Polycefin family nanodrug is crossing the blood-brain barrier (BBB) for effective brain cancer treatment.
Source: Chou S-T et al, J Control Release. 244: 14-23, 2016
The active drug component blocks several cancer-specific tumor markers at the same time for multiple tumors: EGFR/EGFRvIII-wild/mutated epidermal growth factor receptor, CK2, a master signaling regulator serine-threonine protein kinase, and HER2/neu. A significant survival increase has been shown in tumor-bearing animals (preclinical data) after drug administration. Using this technology, it is possible to block a combination of several unique markers for each patient at the same time, providing a synergistic effect.
The Ljubimova Laboratory has also broken new ground with the discovery of cancer biomarkers to prevent growth and metastasis of brain, breast and lung cancers. For the first time, the team has developed nanomedicine technology to inhibit the synthesis of cancer-specific extracellular matrix protein, laminin-411, and to engineer a novel drug delivery system to reduce gliomas in the brain in vivo. An ongoing clinical trial has evaluated approximately 300 patients for laminin-411 as a glial tumor biomarker, confirming its role as a potential target for cancer treatment.
Fig. 3. Molecular mechanism developed for nanodrug releasing from the endosomes to the cytosol of the cancer cell.
Discovery of the New Cancer Biomarker, Laminin 411
Institute researchers used leading-edge gene-sequencing analysis to discover a new cancer biomarker: laminin-411 (formerly known as laminin-8). Human gliomas and invasive breast cancer excessively produce laminin-411, which plays an important role in the ability of tumor cells to spread and grow (Cancer Res. 2001;61:5601-5610, Breast Cancer Res. 2005;7:411-421). This biomarker was later analyzed in a number of human gliomas and showed a significant correlation with glial tumor grade, time to recurrence and patients' survival times (Cancer 2004;101:604-612, Front Biosci. 2006;11:81-88). Inhibition of this marker and drug delivery into the brain in vivo was developed, and glioma tumor reduction was achieved (PNAS USA, 2010;107:18143-18148). This test is being used to evaluate the biological behavior of gliomas in order to better plan individualized therapeutic treatment and follow-up regimens for each patient. An ongoing clinical trial is underway in the Neurosurgery Department and Pathology and Laboratory Medicine at Cedars-Sinai for laminin-411 as a glial tumor biomarker (about 300 patients have been evaluated).
Nanomedicine research involves collaboration with partners at other institutions, as well as a number of clinical departments at Cedars-Sinai, including Surgery Department, Department of Medicine, Imaging for the Neurosurgery Department, Pathology and Laboratory Medicine, Obstetrics and Gynecology Department and the Department of Biomedical Sciences. Funding for research in the Ljubimova Lab includes a significant level of peer-reviewed grants support from the National Institutes of Health/National Cancer Institute.