P1/2, N=310, Recruiting, Beijing InnoCare Pharma Tech Co., Ltd. | N=42 --> 310

Also, PharmacoGx data indicated that the expression level of SDHB was correlated with drug sensitivity to Crizotinib and Dovitinib. Our findings highlight the potential association between alterations in the expression of genes such as HOXC6, HOXC13, HOXC8, TBX15, SDHB, COX5A, and UQCRC1 and increased mortality rates in CRC patients. As revealed by the PPI network, these genes exhibited the most connections with other genes linked to survival.

Pan-TRK IHC shows some utility as a diagnostic and surrogate marker for NTRK screening however, physiologic or non-specific expression may lead to false-positive results.

Ligand-based virtual screening and molecular docking were performed, resulting in the selection of three lead compounds (CID_135698391, CID_135453100, CID_136599608) with superior binding affinities compared to the reference compound dovitinib...Overall, small-molecule compounds CID_135453100 and CID_136599608 showed promising binding interactions and stability, suggesting their potential as direct inhibitors of STK17B. These findings could contribute to the exploration of novel therapeutic options targeting STK17B in cancer treatment.Communicated by Ramaswamy H. Sarma.

No NTRK or ALK translocations or increased copy number/amplification were identified in all eight cases which had fluorescence in situ hybridisation and/or next generation sequencing for NTRK1-3 and ALK available for assessment. None of the cases expressed BRAF-V600E.Although our study is limited, our report is the first to document PanTRK expression in AFH in the absence of identifiable NTRK1-3 gene alterations.

Even though pan-TRK immunohistochemical expression is not entirely sensitive or specific for NTRK-rearranged sarcomas, these neoplasms tend to exhibit diffuse staining of moderate/strong intensity, unlike its mimics. Pan-TRK should be performed in monomorphic uterine (corpus and cervix) spindle cell neoplasms that are negative for smooth muscle markers and hormone receptors and positive for CD34 and/ or S100. Ultimately, the diagnosis requires molecular confirmation.

In this study, we use knowledge of the molecular recognition of both protein and RNA targets by dovitinib to design molecules that specifically inhibit the RNA target but lack activity against canonical protein targets in cells. As it is now becoming apparent that RNA can be both an on- and off-target for small molecule medicines, this study lays a foundation to use design principles to maximize desired compound activity while minimizing off-target effects.

CANTRK illustrates a successful strategy to accelerate the multicenter harmonization and implementation of pan-TRK immunohistochemical screening that achieves high diagnostic sensitivity by using laboratory-developed tests where laboratories used centrally developed reference materials. The measurement of analytic sensitivity by using TRK calibrators provided additional insights into IHC protocol performance.

It was found that nitrogen-containing aromatic heterocyclic and benzo heterocyclic structures play a crucial role in enhancing the activity of TRK inhibitors. Workflow for generating predictive models for TRK inhibitors.

Herein, we used a tetracycline (Tet)-inducible RNAi-mediated expression silencing cell system to investigate how UBR5 enables postsurgical mammary tumor metastatic growth in mouse lungs without the continuous influence of the primary lesion...Moreover, doxycycline-induced UBR5 expression knockdown in metastatic cells in the lungs, following removing the primary tumors, resulted in increased apoptosis, decreased proliferation and prolonged survival, whereas silencing the expression of cell division cycle 73 (CDC73), a tumor suppressor and E3 ligase substrate of UBR5, reversed these effects. Transcriptome analyses revealed a prominent role of the p53 pathway in dovitinib-induced apoptosis of tumor cells differentially regulated by UBR5 and CDC73...Furthermore, a xenograft model of human TNBC recapitulated the metastatic properties and characteristics of the unique UBR5-CDC73 functional antagonism. This study reveals the novel and critical roles and intricate relationships of UBR5, CDC73 and p53 in postsurgical breast cancer metastasis and indicates the potential of targeting this pathway in cancer therapy.

"Allarity Therapeutics, Inc...is pleased to announce that the Company has been invited to give a presentation at Biomarkers Europe 2023. The presentation will focus on Allarity’s development of drug-specific DRP^® companion diagnostics (CDx) for oncology therapeutics, featuring clinical validation for several exemplary DRP^® CDx....In addition to its presentation, Allarity is honored to participate in a panel discussion titled 'Prediction Of Drug Response Using An Ex Vivo Organ Culture (EVOC) On Oncology Patients, Clinical Trial Development And Patient Testing' at the same conference."

The DRP-Dovitinib shows promise as a potential biomarker for identifying advanced RCC patients most likely to experience clinical benefit from dovitinib treatment, subject to confirmation in an independent prospective trial of dovitinib in RCC patients.

P=NA | N=135 | "Allarity Therapeutics...announced today the publication of its clinical validation of a novel drug-specific DRP®-companion diagnostic (CDx) for dovitinib in the peer-reviewed journal PLOS ONE. Data showed that the DRP®-Dovitinib CDx was able to identify a subgroup of advanced renal cell carcinoma (RCC) patients that have improved clinical benefit from treatment with dovitinib, as compared to unselected patients....In the study evaluating pre-treatment biopsies of 135 advanced RCC patients, the DRP® positive subgroup (indicating that the patient was likely to respond) (N=49) had a median overall survival of 15 months (96% CI 12.94-26.25), whereas the DRP® negative subgroup (N=86) had a median overall survival of 9.13 months (95% CI 7.49-13.2)."

Conclusion This study supports the known conclusion that the diagnosis of a NTRK-related fusion-driven neoplasm cannot be made based solely on the immunohistochemical expression of panTRK. The significance of panTRK immunohistochemical expression in multiple different uterine mesenchymal neoplasms without NTRK-related fusions is, as of yet, not entirely clear but continues to raise questions regarding a) the exact mechanisms causing this, and b) the possible therapeutic utility of selective TRK inhibitors in the treatment of these neoplasms.

Our results indicate that pan-Trk nuclear staining is highly specific for SCB. In low-grade to intermediate-grade IBCs that share histological features with SCB, adding pan-Trk to a routing panel of estrogen receptor/progesterone receptor/HER2 is highly diagnostic. Our results also support using pan-Trk IHC to differentiate SCB from its triple-negative histological mimickers, such as adenoid cystic carcinoma, matrix-producing carcinoma, apocrine carcinoma and acinic cell carcinoma.

These data lead to suggest that IHC with VENTANA pan-TRK antibody can be a reliable screening tool for the identification of patients potentially bearing NTRK rearranged tumours.

Pan-TRK should be performed in uterine monomorphic spindle neoplasms negative for smooth muscle markers and hormone receptors and variably positive for CD34 and S100. The diagnosis of an NTRK-rearranged sarcoma requires molecular confirmation but pan-TRK immunohistochemistry is a useful screening tool to direct which cases require molecular testing

Results A total of 79 colorectal cancer patients were included in this study,with the male-to-female ratio of 1.26:1 and the mean age of(57.06±12.74)years(24-83 years).Among them,4 patients received preoperative neoadjuvant therapy.Colonic cancer and rectal cancer occurred in 57(57/79,72.15%,including 31 and 26 in the right colon and left colon,respectively)and 22(22/79,27.85%)patients,respectively.The maximum diameter of tumor varied within the range of 1-20 cm,with the mean of(6.61±3.33)cm.Among the 79 colorectal cancer patients,75(75/79,94.94%)patients showed adenocarcinoma.Lymph node metastasis occurred in 12(12/21,57.14%)out of the 21 patients with severe tumor budding,13(13/23,56.52%)out of the 23 patients with moderate tumor budding,and 2(2/31,6.45%)out of the 31 patients with mild tumor budding,respectively.The lymph node metastasis rate showed differences between the patients with severe/moderate tumor budding and the patients with mild tumor budding(all P<0.001).The IHC staining showed that mismatch repair protein was negative in 10(10/65,15.38%)patients,including 5 patients with both MSH2 and MSH6 negative,4 patients with both MLH1 and PMS2 negative,and 1 patient with MSH6 negative.Pan-TRK was negative in 65 patients.The IHC results of HER2 showed 0 or 1+ in 60 patients and 2+ in 5 patients.FISH showed no positive signal in the 5 patients with HER2 IHC results of 2+.The detection with EBV-encoded small RNA showed positive result in 1(1/65,1.54%)patient. Conclusions Non-specific adenocarcinoma of the right colon is the most common in the patients with colorectal cancer resected in Tibet,and 15% of the patients showed mismatch repair protein defects.EBV-associated colorectal carcer is rare,Pan-TRK expression and HER2 gene amplification are seldom.The colorectal cancer patients with moderate and severe tumor budding are more likely to have lymph node metastasis.

Our findings identified potential druggable targets relevant to patient groups, especially for refractory immune desert-type/ 'cold' GC. Dovitinib, an RTK inhibitor, sensitised desert-type immune-cold GC to CTLA4 blockade by restricting EMT and recruiting T cells.

No abstract available

For patients of IMDDR subtype, we recommend the combination of venetoclax and PHA-665752. A-674563 and dovitinib could be combined with DDR inhibitors to treat patients in IMDDR subtype. Moreover, single-cell analysis revealed that there are more immune cells clustered in the IMDDR subtype and higher number of monocyte-like cells, which exert immunosuppressive effects, in the IMDDR subtype. These findings can be applied for molecular stratification of patients and might contribute to the development of personalized targeted therapies for AML.

The rate of false negative cases was lower when pan-Trk staining was assessed with the lowest positivity threshold (≥1%). In conclusion, most evaluated pan-Trk IHC LDTs were able to detect NTRK3-fusion proteins, however a significant analytical variability was observed between antibodies, platforms and centers.

NTRK fusions were identified in 4 patients positive for the pan-TRK antibody through NGS. IHC tests (with the pan-TRK antibody) are a sensitive and specific method for identifying the presence of NTRK1-3 fusions.

Conclusively, EMC may manifest superficial or osseous lesions harboring EWSR1::NR4A3, under-recognized solid or anaplastic histology, and pan-Trk expression, posing tremendous challenges. Most TAF15::NR4A3-positive cases were >10 cm in size, i.e., the crucial independent prognosticator, while pathogenic KIT mutation rarely occurred.

Histological clues and IHC helped streamline a small subset of potential candidates. Although FISH is a powerful technology for identifying NTRK rearrangements, RNA-/DNA-based NGS is recommended for highly suspected cases in which FISH signal patterns are not discernible as classic positive patterns, particularly if targeted therapy is considered.

P1/2, N=55, Recruiting, Beijing InnoCare Pharma Tech Co., Ltd.

Given the therapeutic importance, testing for NTRK rearrangements in daily practice has become necessary and despite IHC being a fast and affordable tool, using it in routine diagnostics is complicated and requires a high level of expertise.

Our study illustrates, albeit extremely rare, NTRK rearranged neoplasm can arise as a primary bony lesion. In addition, we describe a novel HMBOX1::NTRK3 fusion which has not been documented before.

One patient with a high-grade tumor developed distant metastasis. Molecular testing for various kinase fusions should be considered for S100+/CD34+ spindle cell neoplasms with perivascular hyalinization and staghorn vessels, as pan-TRK positivity is seen only in NTRK fusions.

Compared with FISH and IHC, NGS is preferred for screening WT GISTs, including NTRK rearrangements. However, since GISTs with NTRK fusions are rare, further studies including more samples and mechanistic investigations should be conducted in the future.

These patients may potentially benefit from immune checkpoint inhibitor therapy. Frequent HER2-low may offer novel anti-HER2 treatment options.

Immunohistochemical staining of a biomarker panel, including ER, PR, HER2, Ki-67, S-100 and pan-TRK, can be used as an auxiliary diagnostic tool, and FISH detection can be used as a diagnostic tool. ETV6-NTRK3 gene fusion involving multiple sites may drive tumorigenesis, while mutations in the TERT promoter region may be a factor driving tumor progression.

TP53 mutation and hepatocellular carcinoma-related pathway may play an important role in the poor prognosis of GAED, which belonging to chromosomally unstable subtype. In addition to anti-HER2 therapy, targeted-TRK and immunotherapy may be the efficient treatments for patients with GAED in the future.

While low expression with Pan-TRK is common in TNBC, intermediate to high expression is rare (<5%). Carcinomas with no special type morphology and intermediate to high Pan-TRK expression should be tested for fusion transcript for potential therapeutic value.

PLAG1-US tend to present as large uterine masses and frequently behave aggressively. Their heterogeneous morphology encompasses a much broader spectrum than previously reported, and also includes heterologous CHS or adipocytic/LPS differentiation. Many cases lack convincing SMI or expression of SMM altogether.

Pan-Trk IHC has outstanding sensitivity for NTRK fusions detection, regardless of staining pattern, and can be used as an inexpensive screening test for NTRK fusions. Pan-Trk IHC has superior sensitivity compared to Idylla GeneFusion assay, especially for NTRK2 fusion detection. Interestingly, IHC+/NGS fusion- cases may have other kinase alterations, including fusions and copy number gains.

Our results indicate that positive nuclear staining for pan-Trk is highly specific for secretory carcinoma. In low to intermediate grade invasive breast carcinomas that share histologic features with secretory carcinomas, the addition of pan-Trk to a routing panel of ER/PR/HER2 is highly diagnostic. Our results also support that pan-Trk can differentiate secretory carcinoma from its triple-negative histological mimics such as adenoid cystic carcinoma, matrix-producing carcinoma and apocrine carcinoma, although this finding needs to be validated in larger studies.

Targeted therapies for this mechanism have been designed and developed in preclinical and clinical studies, including selective TrkB inhibitors and pan-TRK inhibitors. This review describes the gene structure, biological function, abnormal TrkB activation mechanism, and current-related targeted therapies in neurogenic tumours.

Despite 34 MCCs showing pan-TRK expression, NTRK fusions were not found in any cases. As in other tumors with neural differentiation, TRK expression seems to be physiological and not caused by gene fusions.

We selected 3 NET organoids (NET16, NET17 and NET18) to test the activity of select drugs: dovitinib (VEGFR inhibitor), vistusertib (mTOR inhibitor), cobimetinib (mitogen-activated protein kinase 1 inhibitor) and TAK243 (ubiquitin activating enzyme inhibitor). Tumor heterogeneity may be contributing to the differences seen in the drug response between the three NET organoids and requires further evaluation. Replication of these studies in a larger subset of patient samples and drug combination studies will be important for the advancement of therapeutics in NETs.