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

Adashek, Jacob J.; Sapkota, Surendra; Luna, Licia P.; Seiwert, Tanguy Y.

doi:10.1038/s41698-023-00378-9

Cited by 6 publications

(3 citation statements)

References 26 publications

(36 reference statements)

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“…NRG1 fusion-bearing cancers may be therapeutically important. Fusions of several different gene types (e.g., BCR-ABL , NTRK , and RET fusions) are known drivers of cancer, and several successful therapies have been developed to target them [ 62 – 69 ]. Moreover, a recent study suggested that not targeting a fusion, if present, is associated with poorer clinical outcome even when genomic co-alterations are targeted [ 62 ].…”

Section: Main Textmentioning

confidence: 99%

Neuregulin-1 and ALS19 (ERBB4): at the crossroads of amyotrophic lateral sclerosis and cancer

Adashek,

Pandya,

Maragakis

et al. 2024

BMC Med

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Background Neuregulin-1 (NRG1) is implicated in both cancer and neurologic diseases such as amyotrophic lateral sclerosis (ALS); however, to date, there has been little cross-field discussion between neurology and oncology in regard to these genes and their functions. Main body Approximately 0.15–0.5% of cancers harbor NRG1 fusions that upregulate NRG1 activity and hence that of the cognate ERBB3/ERBB4 (HER3/HER4) receptors; abrogating this activity with small molecule inhibitors/antibodies shows preliminary tissue-agnostic anti-cancer activity. Notably, ERBB/HER pharmacologic suppression is devoid of neurologic toxicity. Even so, in ALS, attenuated ERBB4/HER4 receptor activity (due to loss-of-function germline mutations or other mechanisms in sporadic disease) is implicated; indeed, ERBB4/HER4 is designated ALS19. Further, secreted-type NRG1 isoforms may be upregulated (perhaps via a feedback loop) and could contribute to ALS pathogenesis through aberrant glial cell stimulation via enhanced activity of other (e.g., ERBB1-3/HER1-3) receptors and downstream pathways. Hence, pan-ERBB inhibitors, already in use for cancer, may be agents worthy of testing in ALS. Conclusion Common signaling cascades between cancer and ALS may represent novel therapeutic targets for both diseases.

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Section: Main Textmentioning

confidence: 99%

Neuregulin-1 and ALS19 (ERBB4): at the crossroads of amyotrophic lateral sclerosis and cancer

Adashek,

Pandya,

Maragakis

et al. 2024

BMC Med

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“…Although rare, ALK translocations represent an important therapeutic target in many solid tumors beyond NSCLC. For example, rare cancers such as papillary renal cell carcinoma and salivary ductal carcinoma have also shown sensitivity to alectinib [103,110].…”

Section: Alkmentioning

confidence: 99%

Agnostic Approvals in Oncology: Getting the Right Drug to the Right Patient with the Right Genomics

et al. 2023

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(1) Background: The oncology field has drastically changed with the advent of precision medicine, led by the discovery of druggable genes or immune targets assessed through next-generation sequencing. Biomarker-based treatments are increasingly emerging, and currently, six tissue-agnostic therapies are FDA-approved. (2) Methods: We performed a review of the literature and reported the trials that led to the approval of tissue-agnostic treatments and ongoing clinical trials currently investigating novel biomarker-based approaches. (3) Results: We discussed the approval of agnostic treatments: pembrolizumab and dostarlimab for MMRd/MSI-H, pembrolizumab for TMB-H, larotrectinib and entrectinib for NTRK-fusions, dabrafenib plus trametinib for BRAF V600E mutation, and selpercatinib for RET fusions. In addition, we reported novel clinical trials of biomarker-based approaches, including ALK, HER2, FGFR, and NRG1. (4) Conclusions: Precision medicine is constantly evolving, and with the improvement of diagnostic tools that allow a wider genomic definition of the tumor, tissue-agnostic targeted therapies are a promising treatment strategy tailored to the specific tumor genomic profile, leading to improved survival outcomes.

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“…From a tumor biology perspective, the concern is a lack of actionable targets. NGS has been widely recognized in solid tumors as a way to identify clinically actionable genomic alterations [ 88 , 89 ], especially for tissue agnostic agents [ 90 , 91 ]. It has been reported previously that the rate of such alterations may vary from 40 to 94% [ 92 ].…”

Section: Mirvetuximab Soravtansine (Elahere™)mentioning

confidence: 99%

Antibody-Drug Conjugates in Solid Tumor Oncology: An Effectiveness Payday with a Targeted Payload

Kondrashov,

Sapkota,

Sharma

et al. 2023

Pharmaceutics

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Antibody–drug conjugates (ADCs) are at the forefront of the drug development revolution occurring in oncology. Formed from three main components—an antibody, a linker molecule, and a cytotoxic agent (“payload”), ADCs have the unique ability to deliver cytotoxic agents to cells expressing a specific antigen, a great leap forward from traditional chemotherapeutic approaches that cause widespread effects without specificity. A variety of payloads can be used, including most frequently microtubular inhibitors (auristatins and maytansinoids), as well as topoisomerase inhibitors and alkylating agents. Finally, linkers play a critical role in the ADCs’ effect, as cleavable moieties that serve as linkers impact site-specific activation as well as bystander killing effects, an upshot that is especially important in solid tumors that often express a variety of antigens. While ADCs were initially used in hematologic malignancies, their utility has been demonstrated in multiple solid tumor malignancies, including breast, gastrointestinal, lung, cervical, ovarian, and urothelial cancers. Currently, six ADCs are FDA-approved for the treatment of solid tumors: ado-trastuzumab emtansine and trastuzumab deruxtecan, both anti-HER2; enfortumab-vedotin, targeting nectin-4; sacituzuzmab govitecan, targeting Trop2; tisotumab vedotin, targeting tissue factor; and mirvetuximab soravtansine, targeting folate receptor-alpha. Although they demonstrate utility and tolerable safety profiles, ADCs may become ineffective as tumor cells undergo evolution to avoid expressing the specific antigen being targeted. Furthermore, the current cost of ADCs can be limiting their reach. Here, we review the structure and functions of ADCs, as well as ongoing clinical investigations into novel ADCs and their potential as treatments of solid malignancies.

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

Cited by 6 publications

References 26 publications

Neuregulin-1 and ALS19 (ERBB4): at the crossroads of amyotrophic lateral sclerosis and cancer

Neuregulin-1 and ALS19 (ERBB4): at the crossroads of amyotrophic lateral sclerosis and cancer

Agnostic Approvals in Oncology: Getting the Right Drug to the Right Patient with the Right Genomics

Antibody-Drug Conjugates in Solid Tumor Oncology: An Effectiveness Payday with a Targeted Payload

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