It is now undeniable that cancers affecting the central nervous system are gradually stricking more patients.
In developed countries, from 5 to 11/100000 patients are diagnosed each year with a primary invasive and very aggressive Glioblastoma Multiforme. It is also known that peripheral cancers can colonize the brain at an advanced stage of the disease. Despite a globally longer survival of patients suffering of breast and lung cancers or melanoma, up to 25% patients will develop incurable brain metastases.
The actual difficulty faced by the medical community is that each tumour is unique. Nowadays, the genetic, cellular and histology profiling of patients allows a classification of primary brain tumors into different grades. Nevertheless, it has been recently discovered that the intra-tumoral heterogeneity is one of the reasons for tumour resistance to chemotherapies and eventually recurrence. This particular patient-specific heterogeneity is a source of challenge for the anticancer drugs efficacy. In case of brain metastases of peripheral neoplasms, defining a brain-metastasis molecular and cellular signature requires first to fully understand the initial neoplastic bed and the tumour cells spreading mechanisms.
The Laakkonen Lab works on the characterization of new molecular targets involved in this tumoural expansion. From this acquired understanding of the invasion mechanisms, we propose to develop new targeting agents, allowing to specifically aim at drug-resistant cell population, recurrent cancer stem cells or non-resected invasive cells. Such targeting agents would be a part of the future perspective of a personalized medicine for each patient.
Microphotography of a whole mouse brain section (white cells) illustrating the growth and invasion of human, patient-derived glioblastoma cells (in red).
Brain metastatic lesions and high grade brain tumors have the capability to invade the brain parenchyma. They can home to a vascular niche and generate radio/chemotherapy resistant relapses. Such metastases usually can't be detected in the clinics before it's too late, i.e. when the tumor has already reach a large size.
It is thus proposed that drugs and/or drug conjugates would exhibit a targeting fragment specific to a molecular marker of metastatic/invasive tumor cells. This molecular fragment, called peptide, would home to the cancer cells and induce a targeted death of such cells.
For instance, the Laakkonen lab. has recently identified several peptide sequences that selectively home to the co-optive glioma cells, which use the brain blood vessels as a railroad to invade the brain. Moreover, the phage display technology used in the lab allows the discovery of hundreds of new peptide sequences that specifically bind to peripheral, central and/or metastatic lesions. Such peptides can exhibit specificity to a type of cancer, one patient tumor, or a tumor microenvironment.
Such peptides are thus conjugated to chemotherapies, nanocarriers or engineered extracellular vesicules and validated in patient-derived preclinical models.