Interferon-beta inhibits the expansion of cancer stem-cells

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 DESCRIPTION (provided by applicant): There will be an estimated 585,720 deaths due to cancer in the United States this year resulting from tumors that regrow after therapy. Most patients suffering from cancer respond initially to treatment resulting in shrinking tumors. In some cases, tumors are completely eliminated or tumor shrinkage is maintained resulting in an effective cure for the patient. However, many tumors will eventually switch from shrinkage to regrowth resulting in tumors that are resistant to therapy. The initial response to treatment results from successful killing of bulk tumor cells, but a subset of tumor cells, the cancer stem cells (CSC), are not sensitive to current therapies. In fact, treatment often causes the expansion of CSC populations through TGFβ signaling. The expansion of surviving CSC seeds the regrowth of tumors that are resistant to therapy. Identifying new therapies that inhibit CSC expansion would prevent the regrowth of resistant tumors significantly improving the number of effective cures following cancer treatment. An innovative model was used to identify factors that could inhibit the expansion of CSC driven by TGFβ signaling following treatment. IFNβ, an important factor in immune system responses, was shown to prevent the expansion of CSC driven by TGFβ. Therefore, we hypothesize that IFNβ inhibits TGFβ signaling and will prevent the regrowth of resistant tumors following treatment. Two aims have been developed to test this hypothesis. Aim 1 will determine: (1) how IFNβ suppresses TGFβ signaling; and (2) which components of IFNβ signaling are required to suppress the TGFβ signaling. Aim 2 will determine: (1) the optimal dosing for IFNβ to inhibit tumor regrowth; (2) the direct effects of IFβ that inhibit tumor regrowth; and (3) the effect of IFNβ on the immune system that inhibits tumor regrowth. IFNβ has been used alone to treat cancer, because at high doses it inhibits tumor growth. Unfortunately, IFNβ use in humans is limited by side effects at the high doses required to treat tumors. Our data suggests that IFNβ may prevent tumor regrowth at much lower doses. Therefore, we suggest using lower doses of IFNβ in combination with current therapies to inhibit tumor regrowth. Our short-term goal is to demonstrate that adding IFNβ to current treatments for cancer will result in less regrowth of treated tumors in mouse models. Our long-term goal would be to use IFNβ as a combination therapy in human cancers to prevent tumor regrowth and reduce patient death. Since IFNβ is already used in humans, it will be easier to have it tested as a combination therapy at lower doses. Successful completion of this proposal would provide a new treatment to prevent the regrowth of therapy-resistant tumors that cause the majority of patient deaths due to cancer.