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2. Other biology-centric problem areas


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      Problem 2.1.

      The role of cellular metabolism in cancer
          Main questions:

      What is the connection between cancer cell metabolism and growth factor signaling? Is there potential for drugs targeting cell metabolism or metabolism and signaling simultaneously?

      Notes:

      (a) There exist strict diet regimens that can be used to affect patients’ metabolic activities, which have beneficial anti-cancer outcomes but are very difficult to manage. This nutrition approach is currently in use for epilepsy to control seizures. Nutrition as a cancer therapy, or therapy booster.

      (b) For some context about the current questions in cancer metabolism, see the agenda from the Keystone Symposium on ’Cancer and Metabolism’: http://www.keystonesymposia.org/meetings/viewMeetings.cfm?MeetingID=1136


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          Problem 2.2.

          Spatial effects on cancer cells
              Main questions:

          What are the pros and cons of 2D vs. 3D experiments and modeling? Is one or both necessary? What are the effects of mechanical stress, or of a tumor’s necrotic core?

          Notes:

          (a) Notion from the literature that microenvironment can be stressful on tumors, and possible connections with why some therapies might be more effective in a 3D environment – are cells in a 3D environment under more stress (e.g., undergoing necrosis) that makes them more sensitive to drug?

          (b) There are studies emerging from the lab of Doug Lauffenburger (MIT) comparing cell behaviors in 2D vs. 3D environments (e.g., Hughes-Alford and Lauffenburger, 2012).

          (c) 2D vs. 3D cell behaviors are also likely cell line dependent.


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              Problem 2.3.

              Cell cycle-dependent variation in tumor cells.
                  Main questions:

              How might such cell cycle-specific changes affect signaling activity and therapeutic efficacy? How does cell receptor number vary with cell cycle?

              Notes:

              (a) There are published studies about the variability in growth factor receptor expression as a function of stage in the cell cycle. For example, see Dong et al. (1991), or Urdiales et al. (1998).

              (b) There is quite a bit of variability in receptor expression per cell.

              (c) How much of observed cell-cell variability in protein expression is due to variation in cell size?

                  Cite this as: AimPL: Systems approaches to drug discovery and development in oncology, available at http://aimpl.org/systemsoncology.