Cancer: slaying the nine-headed Hydra

Adashek, Jacob J.; Subbiah, Vivek; Westphalen, C. Benedikt; Naing, Aung; Kato, Shumei; Kurzrock, Razelle

doi:10.1016/j.annonc.2022.07.010

Cited by 21 publications

(17 citation statements)

References 80 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our patient continues to have clinical benefit with an ongoing complete response eight months after therapy initiation, which highlights the importance of precision medicine and routine molecular profiling in such cases to address some of the inequities apparent for rare tumors 5,6,9,15,20,[23][24][25][26] . The authors report a case of a patient with ALK-fusion mSDC receiving alectinib and achieving a complete response; additional studies are warranted in this patient population.…”

Section: Discussionmentioning

confidence: 92%

Complete response to alectinib in ALK-fusion metastatic salivary ductal carcinoma

et al. 2023

View full text Add to dashboard Cite

The advent of next-generation sequencing (NGS) has allowed for the identification of novel therapeutic targets for patients with uncommon cancers. It is well known that fusion translocations are potent driver of cancer pathogenesis and can render tumors exquisitely sensitive to matching targeted therapies. Here we describe a patient with ALK-fusion positive widely metastatic salivary ductal carcinoma, who achieved a durable complete response from alectinib, a potent and specific ALK tyrosine kinase inhibitor. This case serves as another reminder that ALK-fusions can be targeted regardless of histology and can afford patients dramatic and durable benefit. It also emphasizes the need for insurance coverage for such beneficial therapies. While ALK fusions are exceedingly rare in salivary ductal carcinoma, the presence of multiple other targetable aberrations supports the recommendation for universal NGS testing for such tumors.

show abstract

Section: Discussionmentioning

confidence: 92%

Complete response to alectinib in ALK-fusion metastatic salivary ductal carcinoma

et al. 2023

View full text Add to dashboard Cite

show abstract

“…There are other subsets of patients with PDAC that would also benefit from molecular tumor board-directed matched therapies, specifically if utilized in earlier lines of cancer treatment. 43 – 46 Furthermore, with the emergence of KRAS-directed targeted therapies, it is expected that increasingly more patients with PDAC can benefit from genomic profiling-directed therapies. 47 We therefore believe that early and universal tumor profiling and genetic testing, followed by discussion in a molecular tumor board, would be the best pathway to assure each patient would receive the best treatment at any given time.…”

Section: Discussionmentioning

confidence: 99%

“…Foremost, there may be value in the continuation of targeted therapy beyond progression with the addition of further therapies directed against emerging resistant clones, as evaluated by serial ctDNA in the case of our patient. 43 , 45 In patient #1 with a somatic EGFR alteration, this is represented by the addition of capmatinib (MET inhibitor) to osimertinib (EGFR inhibitor) upon emergence of MET amplification in ctDNA after treatment with erlotinib. This scenario is similar to that observed in lung cancer, 25 , 27 , 48 but has not previously been reported, to our knowledge, in PDAC.…”

Section: Discussionmentioning

confidence: 99%

“…The latter observation also demonstrates the need for combination therapy (osimertinib plus capmatinib) rather than osimertinib by itself, consistent with prior reports demonstrating that patients whose tumors harbor more than one driver alteration require therapy that addresses as many drivers as possible for optimized outcomes. 43 , 45 Lastly, in selected patients, matched targeted therapy was associated with durable response with good tolerance, raising the question of optimal treatment sequencing with respect to cytotoxic chemotherapy. Prior reports suggested that patients with advanced PDAC treated with matched targeted therapies did best in first line.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Chemotherapy-free treatment targeting fusions and driver mutations in KRAS wild-type pancreatic ductal adenocarcinoma, a case series

Mehdi,

Szabo,

Shreenivas

et al. 2024

Ther Adv Med Oncol

View full text Add to dashboard Cite

Background: KRAS wild-type (WT) pancreatic ductal adenocarcinoma (PDAC) represents a distinct entity with unique biology. The therapeutic impact of matched targeted therapy in these patients in a real-world setting, to date, is less established. Objectives: The aim of our study was to review our institutional database to identify the prevalence of actionable genomic alterations in patients with KRAS-WT tumors and to evaluate the therapeutic impact of matched targeted therapy in these patients. Design: We reviewed electronic medical records of patients with KRAS-WT PDAC and advanced disease ( n = 14) who underwent clinical-grade tissue ± liquid next-generation sequencing (315–648 genes for tissue) between years 2015 and 2021. Methods: Demographic and disease characteristics were summarized using descriptive parameters. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. Results: Of 236 PDAC patients, 14 had advanced/metastatic disease with KRAS-WT tumors. Median age at diagnosis was 66 years. There was a high frequency of potentially actionable genomic alterations, including three (21%) with BRAF alterations, two (14%) with fusions [ RET-PCM1 and FGFR2-POC1B ( N = 1 each)]; and one with a druggable EGFR ( EGFR E746_A755delISERD) variant; two other patients had an STK11 and a MUTYH alteration. Five patients were treated with matched targeted therapy, with three having durable benefit: (i) erlotinib for EGFR-altered tumor, followed by osimertinib/capmatinib when MET amplification emerged (first-line therapy); (ii) pralsetinib for RET fusion (fifth line); and (iii) dabrafenib/trametinib for BRAF N486_P490del (third line). Duration of time on chemotherapy-free matched targeted therapy for these patients was 17+, 11, and 18+ months, respectively. Conclusion: Sustained therapeutic benefit can be achieved in a real-world setting in a subset of patients with advanced/metastatic KRAS-WT PDAC treated with chemotherapy-free matched targeted agents. Prospective studies are warranted.

show abstract

“…Moreover, SHP2 regulates the suppression of immunological checkpoints, inhibiting patients' antitumor immune responses, and making it an attractive therapeutic target [104]. In general, many advanced tumors have more than one altered pathway, and combination strategies matched to the alterations present are associated with better outcomes [107][108][109]. With SHP2, combination therapy has shown greater success than monotherapy in preclinical studies, overcoming drug resistance and issues arising from monotherapy [110].…”

Section: Overcoming Drug Resistance In Solid Tumors: Shp2 Inhibitors ...mentioning

confidence: 99%

Overcoming Immune Checkpoint Therapy Resistance with SHP2 Inhibition in Cancer and Immune Cells: A Review of the Literature and Novel Combinatorial Approaches

Tojjari,

Saeed,

Sadeghipour

et al. 2023

Cancers

View full text Add to dashboard Cite

SHP2 (Src Homology 2 Domain-Containing Phosphatase 2) is a protein tyrosine phosphatase widely expressed in various cell types. SHP2 plays a crucial role in different cellular processes, such as cell proliferation, differentiation, and survival. Aberrant activation of SHP2 has been implicated in multiple human cancers and is considered a promising therapeutic target for treating these malignancies. The PTPN11 gene and functions encode SHP2 as a critical signal transduction regulator that interacts with key signaling molecules in both the RAS/ERK and PD-1/PD-L1 pathways; SHP2 is also implicated in T-cell signaling. SHP2 may be inhibited by molecules that cause allosteric (bind to sites other than the active site and attenuate activation) or orthosteric (bind to the active site and stop activation) inhibition or via potent SHP2 degraders. These inhibitors have anti-proliferative effects in cancer cells and suppress tumor growth in preclinical models. In addition, several SHP2 inhibitors are currently in clinical trials for cancer treatment. This review aims to provide an overview of the current research on SHP2 inhibitors, including their mechanism of action, structure-activity relationships, and clinical development, focusing on immune modulation effects and novel therapeutic strategies in the immune-oncology field.

show abstract

Cancer: slaying the nine-headed Hydra

Cited by 21 publications

References 80 publications

Complete response to alectinib in ALK-fusion metastatic salivary ductal carcinoma

Complete response to alectinib in ALK-fusion metastatic salivary ductal carcinoma

Chemotherapy-free treatment targeting fusions and driver mutations in KRAS wild-type pancreatic ductal adenocarcinoma, a case series

Overcoming Immune Checkpoint Therapy Resistance with SHP2 Inhibition in Cancer and Immune Cells: A Review of the Literature and Novel Combinatorial Approaches

Contact Info

Product

Resources

About