Related Experiment Video

Updated: Aug 23, 2026

In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice
07:02

In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice

Published on: August 23, 2019

Cellular effects and antitumor activity of RET inhibitor RPI-1 on MEN2A-associated medullary thyroid carcinoma

Giuditta Cuccuru1, Cinzia Lanzi, Giuliana Cassinelli

  • 1Preclinical Chemotherapy and Pharmacology Unit, and Nuclear Medicine Unit, Istituto Nazionale Tumori, Milan, Italy.

Journal of the National Cancer Institute
|July 9, 2004
PubMed
Abstract

Insights

RPI-1, a novel Ret tyrosine kinase inhibitor, effectively reduced proliferation and tumor growth in medullary thyroid carcinoma models. This drug shows promise for treating MEN2A-associated cancers due to its antitumor efficacy and oral availability.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The RET proto-oncogene, a receptor tyrosine kinase, is implicated in medullary thyroid carcinoma (MTC) pathogenesis via gene mutations.
  • MTC is a component of multiple endocrine neoplasia type 2 (MEN2) syndromes and exhibits poor response to conventional chemotherapy.
  • RET oncogenic mutants are frequently observed in MEN2A syndrome.

Purpose of the Study:

  • To investigate the cellular effects of RPI-1, a novel 2-indolinone Ret tyrosine kinase inhibitor.
  • To evaluate the antiproliferative and antitumor activities of RPI-1 in preclinical models of MEN2A-associated medullary thyroid carcinoma.

Main Methods:

  • Assessed RPI-1's antiproliferative activity using cell proliferation and anchorage-independent growth assays in NIH3T3 cells with RET C634 mutants and human TT cells with endogenous RET C634W.
  • Examined Ret expression, phosphorylation, and downstream signaling pathways (PLCγ, ERKs, AKT) via immunoblotting.
  • Evaluated the in vivo antitumor activity of oral RPI-1 in nude mice bearing subcutaneous TT xenograft tumors.

Main Results:

  • RPI-1 demonstrated significant antiproliferative effects, with lower IC50 values in RET mutant-expressing cells compared to control cells.
  • RPI-1 treatment led to undetectable Ret protein and tyrosine phosphorylation in NIH3T3 cells and inhibited proliferation and Ret signaling in TT cells.
  • Oral RPI-1 administration in mice resulted in an 81% reduction in TT xenograft tumor growth and decreased calcitonin levels; 25% of treated mice achieved a tumor-free status.

Conclusions:

  • Ret oncoproteins are viable therapeutic targets for MEN2A-associated medullary thyroid carcinoma.
  • RPI-1 exhibits significant antitumor efficacy and favorable oral bioavailability, supporting its potential as a therapeutic agent for MTC.

Related Concept Videos

Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against specific...
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The Retinoblastoma Gene01:20

The Retinoblastoma Gene

Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...