Akademik Veri Yönetim Sistemi
Özçelikkale A. (Yürütücü)
TÜBİTAK Projesi, 2020 - 2023
Initiatives in translational medicine has led to numerous potential cancer treatments based on promising drug candidates and cell-based therapies. On one hand, new nanomedicine with novel drug formulations and nanoparticulate carriers are now rapidly being developed and their efficacies are being demonstrated in preclinical environments. On the other hand, the successful use of gene editing technology in clinical experiments is giving rise to highly potent precision medicine with therapies based on patient-derived cells reprogrammed to target malignancies. However, in both nanomedicine drug formulations and cell-based therapies, the progress of individual treatments towards mainstream clinical use is slow since legitimate concerns over efficacy and safety requires extensive clinical trials. It is not uncommon to uncover problems with therapeutic efficacy or unintended toxicity that were not identified in earlier stages. Such late discoveries not only derail treatment development timeline, but also result in unrecoverable losses in the quality of patient care and dramatically increase the treatment development costs.
At the center of this issue is the critical disconnect between the current preclinical models and rigorous clinical evaluation processes in evaluating effectiveness and safety of novel cancer treatments. In particular, failure of in vitro screening assays and animal models to adequately model hallmarks of human cancer pathophysiology prevent them from reliably predicting behavior of drugs and programmed cells in patient’s body. In this proposal, we aim to address this gap by developing artificial tumor microenvironments recapitulating the cancer pathophysiology with high fidelity and in a controlled and parameterizable manner using microfluidics. The proposed microfluidic platforms will model within an array of microchannels and chambers partitioned by nanoporous membranes specific tissue-tissue interfaces between tumor vasculature, interstitium and lymphatics, dynamic fluid flow and prevailing elevated fluid pressure around the tissue, dense and mechanically stressed extracellular matrix environment and complex gradients of oxygen, nutrients and soluble factors. Research in past decade has established these tumor microenvironmental factors as important moderators of cancer cell behavior and treatment response. Therefore, the proposed platform is expected to deliver improved predictions on key treatment metrics such as drug resistance and tumor progression compared to existing in vitro tumor models while at the same time it will circumvent inherent problems in animal models due to non-human physiology by incorporating cells and biomaterial tissue components with human origin whenever possible.
We
envision these microfluidic devices as versatile treatment test beds for
multitude of cancer types and pathophysiological processes. For validation and establishment of an immediate
use case, we will focus our attention on contemporary drug- and cell-based
immunotherapy on breast cancer and melanoma with targeted therapy and adaptive
cell transfer (ACT), respectively. The validation of these immunotherapy-on-chip
(ITOC) devices will be done by evaluation of on-chip immunotherapeutic drug
efficacy and ACT therapy scenario. Processes on ITOC will be accessible for
observation via light and fluorescence microscopy enabling real-time and
high-content information acquisition with assays for cell viability and
specific markers of treatment mechanisms. Results from ITOC will be compared
with contemporary in vitro 3D
spheroid cultures and animal models from literature. The findings from this
project will help develop new generation of engineered tumor models with
improved predictive power that will not only streamline drug development but
also lead to bedside tools and products for on-demand and patient-specific
treatment planning in clinics.