New approach to acquired drug resistance and toxicity in cancer chemotherapy

Abstract

Acquired drug resistance is a major cause of failure of cancer chemotherapy. Rapidly dividing cancer cells quickly evolve DNA mutations to bypass any single drug targeted metabolic pathway. Several drugs targeting different cancer biomarkers, can be used in combination, to target multiple biomarkers simultaneously, to reduce the tumor’s ability to provide sufficient mutations to evade the simultaneous attack. We hypothesize a new cancer treatment paradigm to overwhelm the ability of the cancer to rapidly evolve sufficient drug resistant pathways to survive. Simultaneous administration of a large array of hundreds of different drugs targeting cancer specific proteins at many sites on these proteins will overwhelm the ability of the cancer cells to survive by simultaneously developing pathways around the effects of all these drugs.We propose that hundreds of small molecule oligonucleotide aptamers be used to selectively bind the surface proteins of cancer cells and hinder their function. Therapeutic radionuclides added to the selected array of aptamers will enhance the cancer treatment. Unlike single drugs which must target a unique focus on a cancer specific protein, radiolabeled aptamers can target anywhere on a cancer specific protein to exert their effects.Toxicity of cancer chemotherapy, another major cause of cancer chemotherapy failure, is caused by binding of chemotherapeutic drugs to components present in normal cells. To reduce therapeutic toxicity, aptamers which bind normal cell proteins can be subtracted from the array of aptamers binding cancer cell proteins. Libraries of hundreds of million inexpensive commercially obtained random aptamers which bind proteins extracted from human cancer tissue, can be selected in vitro. Although the cancer proteins will not retain all of their in vivo configurations, the use of a large array of aptamers will assure that many aptamers will bind many of the in vitro sites that retain their configuration in vivo. Subtraction of aptamers binding to normal cell proteins to reduce toxicity will also remove aptamers binding normal proteins in the cancer cells. The final selected array of hundreds of aptamers will represent aptamers binding only the cancer specific molecules.As proof of principle of our hypothesis, proteins extracted from tumors that develop after implanation of cancer cells in xenogenic mice can be used as targets for multiple rounds of aptamer selection, reimplanation and reselection. To reduce toxicity, aptamers binding to proteins extracted from a collection of many different normal mouse tissues can be subtracted from the array of selected aptamers.