Fudan Cancer Hospital Head and Neck Surgery Leader! For the first time, the molecular typing and precision treatment strategy of medullary thyroid cancer were revealed

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Written by Lily

Recently, researchers from the Department of Head and Neck Surgery of Fudan University Cancer Hospital and other institutions have discovered new pathogenic genes in medullary thyroid cancer through multi-omics joint analysis; For the first time, three types of molecular typing of medullary thyroid cancer were proposed, and the potential precise treatment direction
of each molecular typing was pointed out.

Dilemma in the treatment of medullary thyroid cancer

 01 

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine malignancy
that originates in parafollicular cells (C cells) of the thyroid gland.
Although MTC accounts for less than 3% of all thyroid tumors, it contributes to up to 13% of thyroid tumor deaths
.
Compared with common papillary thyroid carcinoma and relatively "niche" thyroid undifferentiated carcinoma, MTC shows a stronger aggressive clinical course and genetic predisposition - about 25% of MTC occurs in genetic form, and almost all of these mutations are caused by germline mutations in the RET proto-oncogene
.
About 75% of the remaining MTCs exhibited a sporadic pattern, half of which had somatic RET alterations and the remainder were mostly RAS mutations
.

Surgery is the preferred treatment for medullary thyroid cancer, with a 10-year survival rate of more than 80%
for early-stage patients.
However, due to the lack of effective therapeutic targets, patients with advanced MTC who miss the opportunity for surgery often fall into the "no cure" dilemma - at present, knowledge about the MTC genome is still lacking, and RET and RAS are the only universally recognized MTC driver genes
to date.
In 2020, the clinical trials of two highly selective RET inhibitors – cerpatinib and platinib – for the treatment of advanced medullary thyroid cancer with RET gene mutation topped the New England Journal of Medicine and The Lancet Endocrinology, and were accelerated by the FDA for their good trial results
.
However, the indications for these two RET inhibitors are limited to patients with RET gene mutations; About 30% to 50% of patients with MTC do not carry RET mutations, so these patients do not benefit
from these two drugs.
For patients with RET mutations, tyrosine kinase inhibitors such as RET inhibitors eventually develop drug resistance; After the patient is resistant, there is currently no effective second-line drug available
.

The most complete map of medullary thyroid cancer gene variants to date

 02 

In order to solve the challenges in the treatment of medullary thyroid cancer, in recent years, Fudan University Shanghai Cancer Center has cooperated with a number of tertiary hospitals in OTTA (Eastern Thyroid Oncology Specialist Alliance, led by the Department of Head and Neck Surgery, Fudan University Cancer Hospital) to establish a large MTC patient sample bank
.

Based on this large-scale multi-center platform, the research team led by Professor Ji Qinghai, Professor Wang Yu and Deputy Chief Physician Wei Wenjun of the Department of Head and Neck Surgery of Fudan University Cancer Hospital, together with the team of Professor Guo Tiannan of Westlake University, conducted comprehensive genomic, transcriptome, epigenome, proteome and phosphorylated proteomic analysis of a large number of MTC patients, and successfully drew the world's first genomics panorama
of medullary thyroid cancer protein 。 The research team identified new pathogenic genes for MTC, including BRAF and NF1; According to the analysis of protein expression profiling, three types of molecular types of MTC were carried out, which provided important reference evidence
for the precision treatment of MTC.

On November 8, his research results were published in the international authoritative academic journal Cell Discovery (IF:38.
08)
in a research paper entitled "Integrated proteogenomic characterization of medullary thyroid carcinoma".

Zhejiang Cancer Hospital, Changzhou Second People's Hospital, Taizhou People's Hospital, and Peking University Shenzhen Hospital also participated in the study
.

style="margin-bottom: 15px;white-space: normal;box-sizing: border-box;" _msthash="251148" _msttexthash="117960219">The research team sequenced the whole exome of genes on the tumors and paired normal tissues of 102 MTC patients, and used the downstream transcription and proteome sequencing results to jointly analyze the nature of gene mutations, and drew the most comprehensive MTC gene variant map to date, and then found a clear cause
for 91% of patients with medullary cancer.
This study confirmed the pathogenicity of BRAF and NF1 genes in medullary carcinoma and enriched the MTC driver gene profile
.

Professor Ji Qinghai, one of the corresponding authors of the paper and chief expert of the head and neck cancer comprehensive treatment group of Fudan University Cancer Hospital, said: "In previous international studies, due to differences in detection methods and sample size, only about 50%-70% of patients were able to find pathogenic mutations, and almost all of them were concentrated on RET and RAS genes
.
We try to start with big data samples to find more potential targeted therapeutic genes and expand the 'arsenal' of medullary thyroid cancer treatment
.
" ”

Proteome triparting helps a new model of precision diagnosis and treatment of medullary thyroid cancer

 03 

Through proteomic mass spectrometry detection of tumor tissues from 102 MTC patients, the research team found that medullary thyroid cancer showed three types of heterogeneous molecular typing
on protein expression profiles.
This paper analyzes the pathological mechanisms of these three types of MTC molecular typing in depth and points out potential precision treatment strategies
.

The first type of tumor is "metabolic": these patients have significant mutation enrichment of RAS gene, with activation of multiple metabolic pathways, and with activation of MAPK and PI3K/Akt/mTOR pathways, enhanced cell cycle kinase activity, and significantly higher genomic instability
.
These patients may benefit
from drugs that have been applied to other tumors, such as MAPK or PI3K pathway inhibitors, cell cycle inhibitors, or PARP inhibitors.

The second type of tumor is "basal type": the degree of differentiation is higher and the neuroendocrine activity of more myeloid carcinoma origin cells (C cells) is preserved; These patients have the best prognosis, with rarely recurrent metastases
.
The expression of carcinoembryonic antigen (CEA) in such tumors is much higher than that of the other two groups, so the anti-CEA antibody conjugate drugs that have been used in clinical trials of other tumors are worth further attempts
in this group of tumors.

The third type of tumor is called "interstitial type": the expression of most interstitial proteins is significantly increased, and the expression of TNC proteins, which is closely related to tumor metastasis, is nearly 3 times
that of other groups.
It is worth noting that the angiogenesis-related proteins VEGFR and PDGFR are the highest expressed in this type of tumor, and these two proteins are the most important anti-cancer targets of the approved drugs cabozantinib and anlotinib
.
At the same time, the expression of CSF1R in "interstitial" tumors is also relatively high, this protein is one of the targets of the domestic original drug sulfatinib, and a clinical trial led by Professor Ji Qinghai published in the journal Thyroid also showed that sulfatinib is effective
in some patients with medullary cancer.
In summary, "interstitial" tumors are the most promising beneficiary groups
of the above approved or pending targeted drugs.

Research significance

 04 

This study broadened the biological understanding of medullary thyroid cancer (MTC) and proposed precise treatment strategies for different molecular types.
These strategies will support future MTC preclinical studies and clinical trials
from a molecular mechanism.
In addition, this study provides the largest comprehensive collection of MTC tumors to date and can serve as an important resource
for further research into MTC biology and therapeutic vulnerability.

Wang Yu, director of the Department of Head and Neck Surgery, Fudan University Cancer Hospital, one of the corresponding authors of this paper, said that this research is expected to be further clinically promoted and applied in the future, and the Department of Head and Neck Surgery is currently working closely with cooperation to carry out more in-depth basic, clinical and translational research on medullary cancer and other advanced/refractory thyroid cancers, and there will be more results incubation in the future to benefit more patients
.

Resources:

style="margin-bottom: 15px;white-space: normal;box-sizing: border-box;" _msthash="251162" _msttexthash="1782794">https://news.
fudan.
edu.
cn/2022/1108/c5a133083/page.
htm

Note: This article is intended to introduce the progress of medical research and cannot be used as a reference
for treatment options.
If you need health guidance, please go to a regular hospital
.