ELABORATING THE MECHANISM OF CELL KILLING OF A NOVEL CHEMOTHERAPEUTIC DRUG TARGETING BREAST CANCER CELLS

Breast cancer (BC) is the second most commonly diagnosed cancer in women in the world. In 2018, there were more than 2 million new diagnosis. It is estimated that1 in 8 women will develop invasive breast cancer over the course of her lifetime. Traditional treatments of BC include surgery, radiation, and chemotherapy therapy; however, these treatments are non-specific and potentially kill peripheral, healthy cells. More specific treatments are needed, most notably to target a unique feature of the cancer cells. Interestingly, 70% of BC cells upregulate estradiol-dependent pathway, a characteristic essential for rapid cell growth. Current BC drugs, such as Tamoxifen, Faslodex, or Femarahave targeted this pathway to preferentially kill BC cells. However, the problems with these drugs are two-fold. (1) Drugs produce considerable side effects. For example, Femera causes considerable musculoskeletal failures. Tamoxifen is also shown to produce secondary cancer growth, such as endometrial cancer. (2) Breast cancer cells resist drugs very quickly. For instance, one third of women who are treated with Tamoxifen for five years relapse within fifteen years. The resulting tumor then become resistant to Tamoxifen treatment. For these two reasons, there is a need for new chemotherapeutic drugs. Our research group studies a novel estrogen-receptor targeting drug: Estradiol-R-Melex. This compound has the estradiol molecule linked to a DNA alkylating agent, Melex. We connected the two moieties using a linker consisting of various lengths, i.e., one, two, and three methyl groups. The linker length variation is to optimize the cell killing property of our small drug molecule. We hypothesize that Est-n-Melex enters the ER positive cancer cells more rapidly than ER-normal cells.