Breast cancer, in its different forms, affects over 250,000 Americans every year. As of the end of 2020, over 7.8 million women were diagnosed with breast cancer in the past five years, making it the most prevalent cancer globally.
A particularly aggressive and hard-to-treat type of this condition is triple-negative breast cancer (TNBC), which does not contain specific receptors aimed by existing treatments. Due to its rapid growth and metastasis, this cancer is challenging to manage. This leads to limited therapy options and poor prognosis for breast cancer patients.
New Approach to Breast Cancer Treatment
At Johns Hopkins University, researchers developed a new approach to fighting tumors while preserving healthy breast cells. Led by chemical and biomolecular engineering professor Efie Kokkoli from Johns Hopkins Institute for NanoBioTechnology, the team used nanotubes to target both proliferating and senescent TNBC cells with chemotherapy and senolytics.
Senescent cancer cells are cancer cells that stop multiplying after exposure to chemotherapy, making them more resistant to further treatment. They are widely detected in premalignant lesions from cancer patients.
In creating the nanotubes, the experts used single-stranded DNA (ssDNA)-amphiphile structures designed to attach to molecules like water and can self-assemble into hollow tubes. The nanotubes are loaded with chemotherapeutic doxorubicin (DOX) or the senolytic ABT-263. The potential of nanotubes in delivering the senolytic ABT-263 was also investigated since DOX and other basic care treatments like radiation have been documented to prompt senescence.
It was found that nanotubes with ABT-263 effectively kill senescent cancer cells as they were made more susceptible to further treatment from doxorubicin. Unlike free DOX, DOX-intercalated nanotubes were proven to be equally cytotoxic to TNBC cells.
According to Kokkoli, their ssDNA nanotubes serve as a promising delivery vehicle that can be used for targeted delivery of both chemotherapeutics and senolytics to TNBC, offering a direct way to fight resistant types of cancer. Even though the project has not started yet, the research team plans to evaluate this delivery system in animal studies and analyze it in a mouse model of TNBC.
Senolytics for Cancer Therapy
Senolytics refers to a group of mechanistically diverse drugs that can eliminate senescent cells in tumors and various aging-related pathologies. Most senolytics aim at targeting anti-apoptotic proteins which are overexpressed in senescent cells.
Cellular senescence is one of the body's responses to stress elicited by various molecular insults. It has become an essential component of tumor cell biology and has served as an area of active investigation in cancer treatment.
Cancer progression is limited in the induction of senescence, contributing to therapy success. In this process, the cells undergo a prolonged growth arrest while remaining metabolically viable. The result can be identified by an array of phenotypes, such as extensive alterations in gene expression, epigenetic changes, dysregulated metabolism, increased lysosomal biogenesis, and structural changes.
Senescent cells are unique because they stop multiplying but do not die off when they should. Instead, they remain and continue releasing chemicals that can trigger inflammation. However, it was discovered that lingering senescent cells can lead to progression, recurrence, and metastasis.
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