DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Attacking Cancer with Missiles

Posted September 30, 2021

Choi-Fong Cho, Ph.D., Brigham and Women’s Hospital, Harvard Medical School

Dr. Choi-Fong Cho
Dr. Choi-Fong Cho

The prognosis for brain cancer remains poor. Glioblastoma (GBM) comprises the most common brain cancer, with an average survival rate of only 12 to 18 months. Standard treatment includes surgery, followed by radiation and/or chemotherapy. Unfortunately, surgery may not completely remove the brain tumor, due to the invasive nature of GBM. This leads to the eventual recurrence or progression of the disease, prompting aggressive treatments that frequently fail. Secondary symptoms of brain cancer burden the patient, including headaches, personality changes, nausea, and other neurological abnormalities. Although the deployment of chemotherapy into the blood circulation can be beneficial to treat many types of cancer, the issue with brain cancer stems from the barrier that separates the brain tissues from blood. The blood-brain-barrier (BBB) remains a hurdle to overcome in the brain cancer therapy field. In work supported by a Fiscal Year 2018 Peer Reviewed Cancer Research Program Career Development Award, Dr. Choi-Fong Cho and colleagues utilize a high-throughput modeling platform to develop targeted therapeutics. This will advance precision medicine to benefit post-war Veterans and active-duty Service Members.

Dr. Choi-Fong Cho
Radiolabeled (fluorescent) BTP-7 in mice bearing intracranial glioblastoma tumor with axial view of positron emission tomography (PET) image showing high contrast between tumor and brain. (Adapted from von Spreckelsen, Adv. Therap., 2021).

Dr. Cho bases this high-throughput modeling platform off her group’s recently pioneered technology, called the BBB organoid model. Organoid technology incorporates cells that follow genetic instructions to self-organize to form small replicas of organs. Dr. Cho and colleagues generated BBB organoids and found that the organoids have characteristics similar to that seen in native tissue. In order to apply this technology to brain cancer, they plan to incorporate glioma stem cells into the BBB organoids. These novel blood-tumor-barrier (BTB) organoids model how brain tumor cells affect the BBB and provide a screening and analysis tool for drug delivery into brain tumor cells. Using this model, Dr. Cho and colleagues demonstrate how the glioma cells affect the BBB and disrupt its function.

The second step of this work centers on the precise targeting of tumor cells to limit side effects to normal brain tissue, aptly named missile therapy. A recently identified peptide, BTP-7, not only crosses the BBB but also targets brain tumor cells. Peptides, or small chains of amino acids smaller than conventional proteins, are commonly used as therapeutic delivery tools due to their size, ease of design, and low expense. Interestingly, BTP-7 specifically binds to a unique form of Brevican (dg-Bcan), a protein expressed at high levels in high-grade gliomas, but not in normal brain tissue. Dr. Cho and colleagues plan to utilize BTP-7 as a guided “missile” for a targeted approach. The group plans to test new therapeutics conjugated to this missile to assess the therapeutic’s ability to disrupt brain tumor cells without damaging normal healthy brain tissue.

The benefits of this project span from research to patient care. Advancements in the brain cancer field resulting from successful outcomes of the BBB organoid model create new opportunities for therapeutic testing. Furthermore, any development of novel therapeutics could improve clinical treatments for brain cancer, which includes the reduction of burden on the patient from chemotherapy. Overall, this novel technology could greatly enhance quality of life for those stricken with brain cancer.

Link:

Public and Technical Abstracts: Developing Targeted Chemotherapeutics for Malignant Brain Tumors Using an Innovative “Blood-Brain Barrier Organoid” Platform

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Last updated Thursday, September 30, 2021