The key to the next cancer therapy breakthrough? One picture to understand the potential targets of recent clinical transformation of cancer

Target: COL6A3

Disease: Unlimited cancer adoptive T cell therapy targets

Journal/PMID: Science Translational Medicine / 36044599

Discovery: T cell receptor therapy targets intracellular and extracellular antigens, but this antigen peptide fragment must be presented on tumor cells by binding to specific human leukocyte antigen (HLA) molecules to become a peptide-HLA (pHLA) complex to be recognized
by T cells.
Therefore, identifying pHLA complexes that are highly expressed in tumors but rare in healthy tissues with high TCR affinity is one of the keys to the success of
TCR therapy.
After quantifying mass spectrometry-based techniques to analyze and compare intra-tissue pHLA complexes, testing about 1500 tumor and healthy tissue specimens, including tissue from 11 different solid tumor patients, and using artificial intelligence to quantify the copy number of various pHLA complexes in each cell, the researchers found a tumor-specific peptide fragment
presented by HLA-A*02:01.
This fragment comes from the COL6A3 gene, which encodes collagen type 6, and its sixth exon (exon 6) is produced
as a result of selective splicing.
This selective splicing occurs in a variety of solid tumor stromas, but is rare
in healthy tissue.
TCR therapy based on the identified pHLA complex showed good efficacy
in mice with human tumor cells.
The experimental results showed that the tumors of the mice receiving this TCR therapy not only slowed down their growth rate, but also had tumor shrinkage
.
Importantly, the therapy was well tolerated and the researchers did not observe any toxicity
to normal cells.
Therefore, COL6A3 has the potential to be developed as a T cell therapy
for the treatment of different types of solid tumors.

Target: NUFIP1

Disease: Pancreatic cancer

Journal/PMID: Nature Cancer/35982178

Findings: Tumor-associated fibroblasts (CAFs) are one of
the most significant components of the tumor microenvironment in pancreatic cancer.
The researchers found that CAF is important
for the survival of pancreatic cancer cells in the absence of glutamine.
CAF secretes nucleosides through the NUFIP1 protein-dependent autophagy mechanism, which promotes the consumption, utilization and tumor growth of pancreatic cancer cells in glutamine deficiency, which relies on the MYC
gene.
Critically, when targeting the NUFIP1 protein in the tumor stromal of mice with pancreatic cancer in situ, it caused a decrease
in tumor weight.
In addition to demonstrating the importance of multiple metabolic networks in pancreatic cancer for tumor growth, this study also showed that NUFIP1 is a possible target for
pancreatic cancer.

Target: MC5R

Disease: Strengthening cancer immunotherapy

Journal/ PMID: Science/ 35926007

Hypothalamic–pituitary gland secretes a variety of hormones to regulate the immune response, and some of the downstream hormone or effector molecules have increased levels in cancer patients
.
The researchers found that the hypothalamic-pituitary gland can promote myelopoiesis and immunosuppression, which in turn promotes tumor growth
.
The implantation of subcutaneous tumors triggers activation of the hypothalamus in mice, as well as the production of α-melanocyte-stimulating hormone (α-MSH) secreted
by the pituitary gland.
α-MSH promotes myeloid hematopoiesis, myeloid cell accumulation, immunosuppression and tumor growth by acting on melanocortin receptor 5 (MC5R) on myeloid progenitor cells
.
Antagonistic peptides targeting MC5R can enhance the anti-tumor immune response and the efficacy
of PD-1 immunotherapy.
It is worth mentioning that the researchers also found that the level of α-MSH in the serum of cancer patients increased and was positively correlated
with the amount of myeloid suppressor cells circulating in the patient's body.
These findings suggest that neuroendocrine pathways may be involved in suppressing tumor immune responses and that MC5R is a potential target for cancer immunotherapy
.

Target: FBXO42

Disease: Blood cancer

Journal/PMID: Science Advances/36129980

It was found that dysregulation of the Notch-RBPJ information pathway is responsible for many diseases, including cancer, but how this key pathway is regulated in cells, the modification of related proteins, and the interacting proteins are mostly unknown
.
Using proteomic methods, the researchers identified FBXO42 as a new interaction protein
for RBPJ.
FBXO42 catalyzes the formation of polyubiquitination chains linked to lysine-63 (K-63) at RBPJ protein Lys-175, thereby enhancing the interaction between RBPJ and chromatin remodeling complexes, resulting in intracellular chromatin looseness
.
Importantly, when the gene knocks out FBXO42, or pharmacologically inhibits FBXO42's E3 ubiquitin ligase activity, it slows the development of
blood cancers associated with the Notch information pathway in mice.
Therefore, targeting FBXO42 may be a potential target for intervening in the Notch information pathway to treat blood
cancers.

Target: CHRM1

Disease: melanoma

Journal/PMID: Science Advances/36054350

Found that people with light skin have a 30-fold
higher risk of developing melanoma than those with darker skin.
Scientists studying primary melanocytes from people with different shades of skin and preclinical melanoma found that independent of ultraviolet light exposure and melanin (melanin) factors, the intrinsic differences in cells are the key to determining the proliferation ability of light and dark melanocytes and the
transformation into malignant tumors.
The key to this is that dark-skinned melanocytes have high levels of the melanin precursor dihydroxyphenylalanine (DOPA).

Through high-throughput pharmacological and in vivo CRISPR screening, the scientists found that DOPA can limit the proliferation
of melanocytes and melanoma cells by inhibiting muscarinic choline receptor M1 (CHRM1) signaling in cells.
CHRM1 antagonists cause c-MYC and FOXM1 levels to decrease
in melanoma cells.
These two proteins are important proteins
that drive the proliferation of aggressive melanoma cells.
Preclinical mouse models of melanoma have also shown that inhibition of CHRM1 or FOXM1 with small molecules inhibits tumor growth, so CHRM1 may be a new target
for the treatment of melanoma.

It is hoped that these excellent research results can be clinically transformed as soon as possible to benefit more cancer patients suffering from diseases!