Nat Rev Clin Oncol: A New Strategy for the Treatment of Advanced Gastrointestinal Stromal Tumors

background:

background:

Gastrointestinal stromal tumor (GIST), the most common form of sarcoma, was first recognized as a distinct pathological entity in the 1990s, and patients with advanced disease have a very poor prognosis due to the lack of effective medical therapy
.

The discovery of the KIT mutation as the first and most prevalent driver of GIST, and subsequent development of the first KIT tyrosine kinase inhibitor (TKI), imatinib, revolutionized the treatment of patients with this disease

Currently, the FDA has approved 7 drugs for the treatment of advanced GIST (imatinib, sunitinib, regorafenib, ripretinib, avatinib, larotrectinib, and entertinib), all of which are for TKIs
.

Although these drugs are very effective in treating certain subtypes of GIST, challenges remain and new treatments are needed

The FDA has approved 7 drugs for the treatment of advanced GIST (imatinib, sunitinib, regorafenib, ripretinib, avatinib, larotrectinib, and entertinib), all TKIs

Introduction:

On February 30, 2022, Prof.
Michael C.
Heinrich's research group from Oregon Health and Science University Portland VA Healthcare System and Knight Cancer Institute published a paper titled "Nat RevClin Oncol (IF: 66.
7)" A review of "New treatment strategies for advanced-stage gastrointestinal stromal tumors"[1]
.

In this review, the authors discuss the molecular subtypes of GIST and the development of current treatments, as well as their therapeutic limitations

Main results:

Main results:

Biology of GIST
.

Biology of GIST
.

GISTs can occur throughout the gastrointestinal tract, most commonly in the stomach (60 65%) and small intestine (20 35%); however, their specific molecular distribution and biology can vary across anatomical sites
.

The distinct molecular subtypes of GIST are broadly defined as single driver alterations

Molecular phenotype
.

Molecular phenotype
.

KIT-mutant GIST
.

In 1998, the KIT mutation was the first driver mutation identified in gastrointestinal stromal tumors

KIT-mutant GIST

PDGFRA-mutant GIST

SDH-deficient GIST

Figure 1: Overview of GIST Cell Molecular Subtypes

Figure 1: Overview of GIST Cell Molecular Subtypes

Origin of cells
.

Origin of cells
.

Most gastrointestinal stromal tumors arise from the transformation of interstitial cells of Cajal (ICCs), which are located in the gastrointestinal wall and function as peristaltic contraction pacemakers
.
At least four different types of ICC have been identified, including intramuscular ICC (ICC-my), intramuscular ICC (ICC-im), submucosal plexus ICC (ICC-smp), and deep mucosal plexus ICC (ICC-dmp)
.

Notably, the distribution of these ICC classes in the gut varies
.
For example, the stomach contains only ICC-MY and ICC-IM, while the large intestine contains these classes as well as ICC-SMP
.
The small intestine lacks ICC-IM and ICC-SMP, but contains ICC-MY and ICC-DMP
.
All four ICC subtypes express KIT, but only ICC-my and ICC-im can be transformed by KIT mutation
.
For some GIST subtypes, cells of different origins have been proposed
.
In 2005, we identified an ICC-like cell with a CD34+PDGFRA+ immunophenotype in the gastrointestinal tract
.
In addition, telomere hyperplasia was observed in rare germline PDGFRA mutant families, similar to the ICC hyperplasia that occurs in germline KIT mutant individuals
.

Pathobiology
.

Pathobiology
.

In gastrointestinal stromal tumors, RTK-activating mutations lead to ligand-independent kinase activation and increased signaling through downstream proliferation and survival pathways, including PI3K-AKT, JAK-STAT, and RAS-RAF MEK-ERK (MAPK ) cascade
.
Rarely, mutations involving other effectors in these pathways, including PI3K, BRAF, or RAS proteins, or their regulators, such as NF1 (a GTPase-activating protein that inactivates RAS), can also drive oncogenic signaling
.
SDH-null GIST is a molecular subtype that appears to deviate from the canonical RTK signaling-driven tumorigenesis mechanism
.
Functional mutation of any SDH gene results in loss of SDH activity, resulting in accumulation of its substrate succinate and reduction in fumarate production
.

Figure 2: GIST signaling pathways, drug targets and current systemic therapies

Figure 2: GIST signaling pathways, drug targets and current systemic therapies

Lessons learned with imatinib
.

Lessons learned with imatinib
.

Before 2000, no effective drug therapy was available for patients with advanced GIST
.
Gastrointestinal stromal tumors have minimal sensitivity to chemotherapy drugs commonly used to treat other sarcomas
.
Historically, gastrointestinal stromal tumors have also been considered resistant to external radiation therapy
.
Although, recent studies, including a single prospective phase II trial, have shown that radiation therapy can provide palliative disease stabilization in selected patients
.

Includes a single prospective phase II trial that has shown that radiation therapy can provide palliative disease stabilization in selected patients
.

In the early 2000s, the only known effective treatment for GIST was surgery, i.
e.
, palliative selective metastases resection for localized disease or for patients with advanced GIST for therapeutic purposes
.
The discovery of activating KIT mutations in GIST in 1998 led to the hypothesis that KIT inhibitors might be effective in the treatment of this disease
.
Around this time, imatinib was identified as a potent KIT TKI with activity against mutant forms of KIT, and extensive clinical trials were already underway in patients with chronic myeloid leukemia
.

Therefore, imatinib was evaluated as a treatment for GIST in several phase II studies and subsequent several large-cohort international randomized phase III trials
.
In these studies, the imatinib-induced clinical benefit rate (complete response, partial response, or durable stable disease) was 70-84%, and the median progression-free survival (PFS) was 20 months
.

The success of imatinib has major implications for GIST treatment, drug development, and research
.
Ultimately, due to the limitations of imatinib, particularly those related to primary (intrinsic) or secondary (acquired) resistance, the development of all currently approved systemic GIST treatments (both TKIs) has Be inspired
.
These limitations also provide a perspective for considering new treatments
.

Figure 3: Typical patterns and evolution of GIST responses during TKI therapy

Figure 3: Typical patterns and evolution of GIST responses during TKI therapy

New strategies for the treatment of GIST
.

New strategies for the treatment of GIST
.

The limitations of previous GIST treatments provide innovative opportunities for the development of new therapeutic strategies, including those utilizing TKIs, both newly developed and currently available, as well as entirely new approaches in the field of GIST treatment
.
Importantly, although this is not a new strategy, the development of new KIT ​​and/or PDGFRA inhibitors, when used as single agents, capable of controlling a broader spectrum of resistance mutations, remains of great clinical relevance for GIST
.
Currently, at least two novel KIT TKIs are entering clinical trials as single agents in patients with advanced GIST: THE-630 (NCT05160168) and NB003 (formally AZD3229; NCT04936178)
.
Both agents have potent activity in vitro against all reported secondary KIT mutations (with the possible exception of some mutations involving codon 816)
.
This spectrum of activity could theoretically overcome polyclonal resistance in KIT-mutant GIST patients who have progressed following treatment with multiple previous product lines of KIT TKIs
.
If promising clinical activity is found in this population with advanced multidrug-resistant disease, more research may test new drugs in early treatment series that could replace the current standard of care TKIs
.
However, additional compound mutations will eventually lead to clinical resistance, even to these new drugs, similar to that observed with the latest generation of EGFR and ABL1 inhibitors
.

Figure 4: New therapeutic approach utilizing different elements of GIST biology

Figure 4: New therapeutic approach utilizing different elements of GIST biology

Combination therapy with TKIs
.

Combination therapy with TKIs
.

Current KIT TKIs lack activity against all relevant resistance mutations, which limits their effectiveness as single agents
.
However, each agent has a unique spectrum of activity against different KIT variants; therefore, combination therapy is one approach to overcome the challenge of polyclonal drug-resistant and/or drug-resistant cells in gastrointestinal stromal tumors
.
Different combinations of KIT-TKIs have been investigated in vitro and in several clinical studies
.
In a phase I study, Serrano et al investigated a new strategy of alternating sunitinib and regorafenib to overcome the differences involved in patients previously treated with at least imatinib, sunitinib, and regorafenib Polyclonal resistance to secondary KIT mutations
.
Unfortunately, this approach was unsuccessful, possibly due to overlapping toxicities of the two TKIs (gastrointestinal and hand-foot-skin reactions), as well as difficulties in designing a tolerable and effective dosing regimen, although it may also be due to the There were previously exposed tumors and thus may have developed resistance to both drugs
.
More recently, bezuclastinib (previously known as CGT9486 and PLX9486), a type I inhibitor with potent activity against KIT exons 17 and 18 (activation loop) resistance mutations, showed showed good tolerability and clinical activity
.
A type II inhibitor with potent activity against KIT exons 13 and 14 resistance mutations in patients with advanced TKI-refractory GIST
.

Conclusion and Outlook:

Conclusion and Outlook:

Over the past 5 years, we have been able to identify GISTs for oncogenic driver events in 99 % of patients, but our ability to target all driver mutations has lagged behind
.
However, in the past few years, in addition to KIT, new strategies targeting the drivers of GIST have been generated, providing an effective treatment for approximately 80-90% of patients with advanced GIST
.

99

However, the limitations of current TKI therapy challenge long-term disease control, and some subtypes of GIST are inherently insensitive to these drugs
.
Therefore, alternative approaches will be needed to better manage advanced GIST, and as new therapies become available, the optimal treatment will need to be refined
.

 

Original link: https:// link:

references:

references:

[1] Klug LR, Khosroyani HM, Kent JD, Heinrich MC.
New treatment strategies for advanced-stage gastrointestinal stromal tumors.
Nat Rev Clin Oncol.
2022 Feb 25.
doi: 10.
1038/s41571-022-00606-4.
Epub ahead of print.
PMID: 35217782.

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