Targeting a neoantigen derived from a common
            <i>TP53</i>
            mutation

Hsiue, Emily Han‐Chung; Wright, Katharine M.; Douglass, Jacqueline; Hwang, Michael S.; Mog, Brian J.; Pearlman, Alexander H.; Paul, Suman; DiNapoli, Sarah R.; Konig, Maximilian F.; Wang, Qing; Schaefer, A.; Miller, Michelle S.; Skora, Andrew D.; Azurmendi, P. Aitana; Murphy, Michael; Liu, Qiang; Watson, Evangeline; Li, Yana; Pardoll, Drew M.; Bettegowda, Chetan; Papadopoulos, Nickolas; Kinzler, Kenneth W.; Vogelstein, Bert; Gabelli, Sandra B.; Zhou, Shibin

doi:10.1126/science.abc8697

Cited by 244 publications

(212 citation statements)

References 83 publications

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“…Since p53 mutations do not occur in normal, healthy cells, they might serve as tumor-specific neoantigens. As anti-p53 antibodies have been detected in cancer patients (including patients with CRC) and antibodies and T-cell receptors can recognize p53 mutants, vaccines targeting mutant p53 are being evaluated in clinical trials for the treatment of many different types of cancer, including CRC [ 194 , 195 , 196 , 197 , 198 ]. Unfortunately, clinical studies with p53 vaccines so far have not shown convincing results.…”

Section: P53 As a Therapeutic Targetmentioning

confidence: 99%

The Role of p53 Signaling in Colorectal Cancer

Liebl

Hofmann

2021

Cancers

172

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The transcription factor p53 functions as a critical tumor suppressor by orchestrating a plethora of cellular responses such as DNA repair, cell cycle arrest, cellular senescence, cell death, cell differentiation, and metabolism. In unstressed cells, p53 levels are kept low due to its polyubiquitination by the E3 ubiquitin ligase MDM2. In response to various stress signals, including DNA damage and aberrant growth signals, the interaction between p53 and MDM2 is blocked and p53 becomes stabilized, allowing p53 to regulate a diverse set of cellular responses mainly through the transactivation of its target genes. The outcome of p53 activation is controlled by its dynamics, its interactions with other proteins, and post-translational modifications. Due to its involvement in several tumor-suppressing pathways, p53 function is frequently impaired in human cancers. In colorectal cancer (CRC), the TP53 gene is mutated in 43% of tumors, and the remaining tumors often have compromised p53 functioning because of alterations in the genes encoding proteins involved in p53 regulation, such as ATM (13%) or DNA-PKcs (11%). TP53 mutations in CRC are usually missense mutations that impair wild-type p53 function (loss-of-function) and that even might provide neo-morphic (gain-of-function) activities such as promoting cancer cell stemness, cell proliferation, invasion, and metastasis, thereby promoting cancer progression. Although the first compounds targeting p53 are in clinical trials, a better understanding of wild-type and mutant p53 functions will likely pave the way for novel CRC therapies.

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Section: P53 As a Therapeutic Targetmentioning

confidence: 99%

The Role of p53 Signaling in Colorectal Cancer

Liebl

Hofmann

2021

Cancers

172

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“…Recently, Han-Chung Hsiue E. et al published an interesting study where the most common TP53 mutant R175H (in which arginine at position 175 is replaced with histidine) was targeted with a bispecific antibody (H2) [ 197 ]. The highly specific antibody binds to human leukocyte antigen-A (HLA-A) allele on the cell surface, which presents peptide fragments of the TP53 R175H mutant, while its other domain binds to a T-cell receptor to trigger an antitumor response.…”

Section: P53 As a Druggable Targetmentioning

confidence: 99%

The Role of p53 Dysfunction in Colorectal Cancer and Its Implication for Therapy

Michel

Kaps

Maderer

et al. 2021

Cancers

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Colorectal cancer (CRC) is one of the most common and fatal cancers worldwide. The carcinogenesis of CRC is based on a stepwise accumulation of mutations, leading either to an activation of oncogenes or a deactivation of suppressor genes. The loss of genetic stability triggers activation of proto-oncogenes (e.g., KRAS) and inactivation of tumor suppression genes, namely TP53 and APC, which together drive the transition from adenoma to adenocarcinoma. On the one hand, p53 mutations confer resistance to classical chemotherapy but, on the other hand, they open the door for immunotherapy, as p53-mutated tumors are rich in neoantigens. Aberrant function of the TP53 gene product, p53, also affects stromal and non-stromal cells in the tumor microenvironment. Cancer-associated fibroblasts together with other immunosuppressive cells become valuable assets for the tumor by p53-mediated tumor signaling. In this review, we address the manifold implications of p53 mutations in CRC regarding therapy, treatment response and personalized medicine.

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“…They have developed a specific bispecific single-chain diabody (SCDB) antibody that targets TP53 and RAS mutations. This bispecific antibody can specifically recognize and activate T cells in vitro and in mice, exerting good anti-tumour effects without cross-reactivity and with a good safety profile (91,92).…”

Section: Advances In the Study Of Neoantigensmentioning

confidence: 99%

Neoantigen: A New Breakthrough in Tumor Immunotherapy

et al. 2021

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Cancer immunotherapy works by stimulating and strengthening the body’s anti-tumor immune response to eliminate cancer cells. Over the past few decades, immunotherapy has shown remarkable efficacy in the treatment of cancer, particularly the success of immune checkpoint blockade targeting CTLA-4, PD-1 and PDL1, which has led to a breakthrough in tumor immunotherapy. Tumor neoantigens, a new approach to tumor immunotherapy, include antigens produced by tumor viruses integrated into the genome and antigens produced by mutant proteins, which are abundantly expressed only in tumor cells and have strong immunogenicity and tumor heterogeneity. A growing number of studies have highlighted the relationship between neoantigens and T cells’ recognition of cancer cells. Vaccines developed against neoantigens are now being used in clinical trials in various solid tumors. In this review, we summarized the latest advances in the classification of immunotherapy and the process of classification, identification and synthesis of tumor-specific neoantigens, as well as their role in current cancer immunotherapy. Finally, the application prospects and existing problems of neoantigens were discussed.

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Targeting a neoantigen derived from a common TP53 mutation

Cited by 244 publications

References 83 publications

The Role of p53 Signaling in Colorectal Cancer

The Role of p53 Signaling in Colorectal Cancer

The Role of p53 Dysfunction in Colorectal Cancer and Its Implication for Therapy

Neoantigen: A New Breakthrough in Tumor Immunotherapy

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