RNA Vaccine Design Against Novel Onco-Antigens in Breast Cancers Involving MAP3K1

Abstract:

Breast cancer is the most common form of cancer in women in the USA.  In 2021, the estimated number of new cases in breast cancers in the United States was about 280,000 persons, accounting for nearly 15% of all new cancer cases.  Of all the cancers, breast cancer has seen great strides in treatment and positive prognoses, with a 5-year survival rate of over 90%.  Survivorship is very much driven by cancerous stage, with greater survivorship seen in localized (confined to primary site) or regionalized (spread to regional lymph nodes) stages.  Survivorship dramatically declines however in distant stages in which the cancer has metastasized, with 5-year survival rates at 29%.  Most women from 55 to 74 years of age are at the highest risk for breast cancer diagnoses, accounting for more than half of all new breast cancer cases.  Anatomically, a woman’s breast consists of 15-20 lobes and each lobe is comprised of numerous smaller partitions known as lobules.  Adipose and fibrous tissues sandwich the spaces between the lobules and the milk ducts.  Breast cancer can occur whenever any of these cells divide uncontrollably resulting in an abnormal growth or tumor.  Such tumors may be benign (non-cancerous) or malignant (cancerous).  MAP3K1 is a serine/threonine kinase that makes up a key component of several different signaling pathways, including those that activate NFkB as well as cascades involving ERK and JNK kinases.   Mutations in MAP3K1 are the fourth leading cause of all breast cancers.  When mutations insert or delete nucleotides in non-multiples of three, a frameshift mutation can occur.  Some frameshift mutations can result in an immediate premature stop codon, abbreviating the gene product.  However, other frameshift mutations might result in the generation of a unique stretch of amino acids found nowhere else in the human proteome.  Such a consequence of a frameshift mutation would thus generate a novel, non-self onco-antigen.  We designed an RNA vaccine against one such MAP3K1 frameshift allele linked to breast cancer.  Our RNA cancer vaccine design should in theory help train such an afflicted patient’s immune system, leveraging the cell-mediated response against any breast cancer cells presenting such neo-antigens via MHC class I molecules.