On systems and control approaches to therapeutic gain.
BACKGROUND
Mathematical models of cancer relevant processes are being developed at an increasing rate. Conceptual frameworks are needed to support new treatment designs based on such models.


METHODS
A modern control perspective is used to formulate two therapeutic gain strategies.


RESULTS
Two conceptually distinct therapeutic gain strategies are provided. The first is direct in that its goal is to kill cancer cells more so than normal cells, the second is indirect in that its goal is to achieve implicit therapeutic gains by transferring states of cancer cells of non-curable cases to a target state defined by the cancer cells of curable cases. The direct strategy requires models that connect anti-cancer agents to an endpoint that is modulated by the cause of the cancer and that correlates with cell death. It is an abstraction of a strategy for treating mismatch repair (MMR) deficient cancers with iodinated uridine (IUdR); IU-DNA correlates with radiation induced cell killing and MMR modulates the relationship between IUdR and IU-DNA because loss of MMR decreases the removal of IU from the DNA. The second strategy is indirect. It assumes that non-curable patient outcomes will improve if the states of their malignant cells are first transferred toward a state that is similar to that of a curable patient. This strategy is difficult to employ because it requires a model that relates drugs to determinants of differences in patient survival times. It is an abstraction of a strategy for treating BCR-ABL pro-B cell childhood leukemia patients using curable cases as the guides.


CONCLUSIONS
Cancer therapeutic gain problem formulations define the purpose, and thus the scope, of cancer process modeling. Their abstractions facilitate considerations of alternative treatment strategies and support syntheses of learning experiences across different cancers.
Radivoyevitch
Tomas
T
Department of Epidemiology and Biostatistics Case Western Reserve University, Cleveland, Ohio 44106, USA. radivot@hal.cwru.edu
Loparo
Kenneth A
KA
Jackson
Robert C
RC
Sedwick
W David
WD
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005492:Folic Acid / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007065:Idoxuridine / Q000627:therapeutic use; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D049490:Systems Biology / Q000379:methods*; D013598:Systems Theory; D000097764:ETS Translocation Variant 6 Protein
D000970:Antineoplastic Agents; D050676:Core Binding Factor Alpha 2 Subunit; D004273:DNA, Neoplasm; D005492:Folic Acid; D016044:Fusion Proteins, bcr-abl; D007065:Idoxuridine; D015514:Oncogene Proteins, Fusion; D011838:Radiation-Sensitizing Agents; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein