Drugs that inhibit insulin-like growth factor 1 (IGFI) receptor IGFIR were encouraging in early trials, but predictive biomarkers were lacking and the drugs provided insufficient benefit in unselected patients. In this study, we used genetic screening and downstream validation to identify the WNT pathway element DVL3 as a mediator of resistance to IGFIR inhibition. Sensitivity to IGFIR inhibition was enhanced specifically in vitro and in vivo by genetic or pharmacologic blockade of DVL3. In breast and prostate cancer cells, sensitization tracked with enhanced MEK–ERK activation and relied upon MEK activity and DVL3 expression. Mechanistic investigations showed that DVL3 is present in an adaptor complex that links IGFIR to RAS, which includes Shc, growth factor receptor–bound-2 (Grb2), son-of-sevenless (SOS), and the tumor suppressor DAB2. Dual DVL and DAB2 blockade synergized in activating ERKs and sensitizing cells to IGFIR inhibition, suggesting a nonredundant role for DVL3 in the Shc–Grb2–SOS complex. Clinically, tumors that responded to IGFIR inhibition contained relatively lower levels of DVL3 protein than resistant tumors, and DVL3 levels in tumors correlated inversely with progression-free survival in patients treated with IGFIR antibodies. Because IGFIR does not contain activating mutations analogous to EGFR variants associated with response to EGFR inhibitors, we suggest that IGF signaling achieves an equivalent integration at the postreceptor level through adaptor protein complexes, influencing cellular dependence on the IGF axis and identifying a patient population with potential to benefit from IGFIR inhibition. Cancer Res; 74(20); 1–12. ©2014 AACR.

Drugs that inhibit IGF-1 receptor IGF-1R were encouraging in early trials, but predictive biomarkers were lacking and the drugs provided insufficient benefit in unselected patients. In this study, we used genetic screening and downstream validation to identify the WNT pathway element DVL3 as a mediator of resistance to IGF-1R inhibition. Sensitivity to IGF-1R inhibition was enhanced specifically in vitro and in vivo by genetic or pharmacological blockade of DVL3. In breast and prostate cancer cells, sensitization tracked with enhanced MEK-ERK activation and relied upon MEK activity and DVL3 expression. Mechanistic investigations showed that DVL3 is present in an adaptor complex that links IGF-1R to RAS, that includes Shc, Grb2, SOS and the tumor suppressor DAB2. Dual DVL and DAB2 blockade synergized in activating ERKs and sensitizing cells to IGF-1R inhibition, suggesting a non-redundant role for DVL3 in the Shc-Grb2-SOS complex. Clinically, tumors that responded to IGF-1R inhibition contained relatively lower levels of DVL3 protein than resistant tumors, and DVL3 levels in tumors correlated inversely with progression-free survival in patients treated with IGF-1R antibodies. Since IGF-1R does not contain activating mutations analogous to EGFR variants associated with response to EGFR inhibitors, we suggest that IGF signaling achieves an equivalent integration at the post-receptor level through adaptor protein complexes, influencing cellular dependence on the IGF axis and identifying a patient population with potential to benefit from IGF-1R inhibition.

In this Mediterranean variation of the classic French vegetable stew, the chicken soaks up the wonderful flavors of ratatouille: peppers, garlic, tomatoes and herbs. This dish is versatile in that it can be made as a one pot meal with chicken or vegetarian (hold the chicken).

Multiple ingredients have properties which may be cancer fighting, antibacterial and/or anti-inflammatory including eggplant, garlic, tomatoes and lemon. Red pepper is twice as high in vitamin C and 11 times higher in beta carotene than green pepper. Zucchini, readily available through local farmers in the summer, and is high in vitamin C.

Chicken Ratatouille

Ingredients

• 1 medium eggplant cut into 1-inch cubes
• 1 teaspoon salt
• 3 tablespoons olive oil
• 1 cut up chicken (approximately 3 lbs)
• 1 chopped onion
• 2 cloves garlic, finely chopped
• 2 peppers (1 green, 1 red), seeded and cubed
• 1 medium zucchini cut in 1-inch cubes
• 2 chopped tomatoes
• Juice of 1 lemon
• 1 tablespoon parsley
• 1/2 teaspoon dried oregano
• 1/2 teaspoon dried basil
• 1/4 teaspoon freshly ground pepper

Directions

1. Lay eggplant cubes on paper towels. Sprinkle with salt and let sit for 15 minutes. Blot excess water. 
2. Heat oil in a Dutch oven over medium heat. Brown chicken pieces in a single layer for about 5 minutes per side. Remove chicken and set aside. 
3. Pour off remaining fat from the Dutch oven. Add onion and garlic. Saute until onion is tender – about 2 minutes. Add green and red bell peppers for another 2 minutes, stirring constantly. Add eggplant, zucchini, tomatoes, parsley, oregano, basil and pepper. Mix well
4. Scoop the chicken to half of the pan. Return chicken to the Dutch oven and cover with vegetables. Season ratatouille with salt to taste. Simmer for 25 minutes until vegetables and chicken are tender. Add the juice of 1 lemon for the last 5 minutes. 

Source: 365 Ways to Cook Chicken by Cheryl Sedaker, Harper Row Publishers, 1986

Debra DeMille, MS, RD, CSO, is a nutritional counselor at the Abramson Cancer Center at Penn Medicine Pennsylvania Hospital. Dietitians at the Abramson Cancer Center provide educational programs about nutrition that are open to patients as well as the community. Cancer-fighting recipes on this blog are the product of the quarterly series “Cooking Nutritious and Delicious Foods,” which promotes seasonal healthy foods with cancer-fighting properties.

In this Mediterranean variation of the classic French vegetable stew, the chicken soaks up the wonderful flavors of ratatouille: peppers, garlic, tomatoes and herbs. This dish is versatile in that it can be made as a one pot meal with chicken or vegetarian (hold the chicken).

Multiple ingredients have properties which may be cancer fighting, antibacterial and/or anti-inflammatory including eggplant, garlic, tomatoes and lemon. Red pepper is twice as high in vitamin C and 11 times higher in beta carotene than green pepper. Zucchini, readily available through local farmers in the summer, and is high in vitamin C.

Chicken Ratatouille

Ingredients

• 1 medium eggplant cut into 1-inch cubes
• 1 teaspoon salt
• 3 tablespoons olive oil
• 1 cut up chicken (approximately 3 lbs)
• 1 chopped onion
• 2 cloves garlic, finely chopped
• 2 peppers (1 green, 1 red), seeded and cubed
• 1 medium zucchini cut in 1-inch cubes
• 2 chopped tomatoes
• Juice of 1 lemon
• 1 tablespoon parsley
• 1/2 teaspoon dried oregano
• 1/2 teaspoon dried basil
• 1/4 teaspoon freshly ground pepper

Directions

1. Lay eggplant cubes on paper towels. Sprinkle with salt and let sit for 15 minutes. Blot excess water. 
2. Heat oil in a Dutch oven over medium heat. Brown chicken pieces in a single layer for about 5 minutes per side. Remove chicken and set aside. 
3. Pour off remaining fat from the Dutch oven. Add onion and garlic. Saute until onion is tender – about 2 minutes. Add green and red bell peppers for another 2 minutes, stirring constantly. Add eggplant, zucchini, tomatoes, parsley, oregano, basil and pepper. Mix well
4. Scoop the chicken to half of the pan. Return chicken to the Dutch oven and cover with vegetables. Season ratatouille with salt to taste. Simmer for 25 minutes until vegetables and chicken are tender. Add the juice of 1 lemon for the last 5 minutes. 

Source: 365 Ways to Cook Chicken by Cheryl Sedaker, Harper Row Publishers, 1986

Debra DeMille, MS, RD, CSO, is a nutritional counselor at the Abramson Cancer Center at Penn Medicine Pennsylvania Hospital. Dietitians at the Abramson Cancer Center provide educational programs about nutrition that are open to patients as well as the community. Cancer-fighting recipes on this blog are the product of the quarterly series “Cooking Nutritious and Delicious Foods,” which promotes seasonal healthy foods with cancer-fighting properties.

SNAIL1 has been suggested to regulate breast cancer metastasis based on analyses of human breast tumor transcriptomes and experiments using cancer cell lines and xenografts. However, in vivo genetic experimental support for a role for SNAIL1 in breast cancer metastasis that develops in an immunocompetent tumor microenvironment has not been determined. To address this question, we created a genetic SNAIL1 model by coupling an endogenous SNAIL1 reporter with an inducible SNAIL1 transgene. Using multiple genetic models of breast cancer, we demonstrated that endogenous SNAIL1 expression was restricted to primary tumors that ultimately disseminate. SNAIL1 gene deletion either during the premalignant phase or after primary tumors have reached a palpable size blunted metastasis, indicating that late metastasis was the main driver of metastasis and that this was dependent on SNAIL1. Importantly, SNAIL1 expression during breast cancer metastasis was transient and forced transient, but not continuous. SNAIL1 expression in breast tumors was sufficient to increase metastasis. Cancer Res; 74(21); 1–11. ©2014 AACR.