#  Scientific Overview: Text  

 



The overarching goal of our Ludwig Center is to develop strategies to overcome the barriers that limit the efficacy of current and emerging cancer therapies. While significant advances have been made in the treatment of cancer, primary and acquired resistance limit our ability to cure disease. Our Center is focused on understanding the fundamental states of resistance that are generated from integration of multiple genetic, epigenetic and microenvironmental programs. This knowledge will then be translated into more effective strategies to treat, and ideally cure, cancer. This will be achieved through highly collaborative teams of multidisciplinary basic scientists and physician-investigators drawn from all the Harvard-affiliated institutions.

What is known about the underlying mechanisms of resistance?:

Cancer therapy resistance poses a significant challenge because there are many distinct mechanisms that protect tumor cells from cancer therapies. These include diverse genetic, epigenetic, and stochastic alterations within tumor cells, as well as a broad spectrum of factors contributed by many diverse cells that are recruited to the tumor microenvironment. This diversity of factors within tumor cells and the tumor microenvironment, as well as the plasticity of tumors which allows them to evolve rapidly, significantly complicates the rational choice of combination therapies to overcome resistance; models have not been sufficiently robust to predict whether inhibition of any one key factor driving resistance would be sufficient to abrogate completely resistance. In addition to this diversity of tumor cell-based mechanisms, there are physical and chemical barriers to effective drug delivery (e.g. poor vascular integrity, interstitial pressure, acidity, and hypoxia). In addition, many factors interfere with effective immune cell surveillance to eliminate tumor cells.

This problem is further complicated by the tumor heterogeneity– this includes heterogeneity between tumors from different individuals, but even more significantly, within an individual tumor, and between tumors at different sites in the same patient. Recent evidence has shown that the vast majority of cells in many tumors do not share a common set of mutations and that multiple branched genetic lineages exist within different regions of each tumor and at metastatic sites of the same tumor. This genetic heterogeneity generates significant diversity in responses to cancer therapies. In addition to the genetic heterogeneity, tumor cells with the same genetic constitution can exist in different states that reflect their differentiated phenotype, their response to matrix and paracrine factors derived from cells within the microenvironment, and their sensitivity or resistance to various perturbations. We propose an integrated cross-disciplinary program to conduct a systemic and comprehensive characterization of the states of tumor resistance in order to develop innovative strategies which can be translated into more effective yet selective tumor cell killing to improve cancer outcomes.



 

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