Elaborating the Mechanism of Cell Killing of a Novel Chemotheraputic Drug Targeting Breast Cancer

Abstract

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.

Comments from Mentors

Phat was a delight to have in my lab and in my classes. It is rare to find a student who takes on a slate of difficult courses just because he or she wants to learn. Phat was one such student, who took courses because they were fun! It didn’t hurt that he was an excellent student as well.

In the lab Phat was stubbornly independent, wanting to figure out everything before I could explain things to him. He found delight in every experimental result and achieved a lot despite an incredibly busy schedule. He spent many nights in the lab doing experiments because there weren’t enough hours in his day. I expect great things from Phat and I look forward to staying in touch with him and following his career.

--Giri Akkaraju