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To determine how various tumor types are affected by dietary resistance, Kalaany injected cells from human prostate, breast, brain, and colon cancers into mice in an experimental protocol used frequently to study human cancers. The mice then ate as much as they liked (control group) or received 60% of the caloric intake of their counterparts (the dietary restriction (DR) group). Both groups ingested the same amounts of vitamins and minerals. After a few weeks, Kalaany saw that the cancers could be divided into DR-sensitive tumors, with significantly lower tumor volumes in the DR mice than in control mice, or DR-resistant tumors, whose sizes were apparently unaffected by normal or restricted diets.

Kalaany then grew the same cancer cells in Petri dishes to see how the DR-sensitive and DR-resistant cancers respond to food-related hormones in the body. The cancers were grown solutions containing increasing amounts of insulin, insulin-like growth factor 1 (IGF1) or in a solution without these hormones. The results supported the previous experiment: those cancer cells that were DR-sensitive in the mice were also stunted by a lack of insulin and IGF1; those cancer cells that were DR-resistant in the mice were unaffected by changes in insulin and IGF1 levels.

Because the difference between the two groups was sensitivity or insensitivity to insulin and IGF1, Kalaany thought the insensitive tumors may have something amiss in a cellular process called the PI3K pathway, which is activated by insulin/IGF1. A search for mutations in two genes found in the PI3K pathway that are often associated with cancer (PI3KCA and PTEN), revealed that DR-resistant cells had mutations in one or the other of the genes, while DR-sensitive cells showed no such mutations.

Using a DR-resistant tumor cell li
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