Targeted Therapy for Adrenocortical Carcinoma: A Genomic-Based Search for Available and Emerging Options
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Linking FDA-Approved Targeted Therapy and Targeted Therapy in Clinical Trials to Their Genetic Targets
2.1.1. FDA-Approved Targeted Therapy
2.1.2. Targeted Therapy Drugs in Current Clinical Trials
2.2. Identification of Altered Druggable Genes in Adrenocortical Carcinoma (ACC)
2.2.1. Alterations in Druggable Genes of ACC Patients
2.2.2. Gain of Function in Druggable Oncogenes
2.2.3. CNV Amplification in Druggable Oncogenes
2.2.4. Mutation Hotspot Analysis
2.3. Drug Response Prediction
2.3.1. Gene Alterations Affecting Drug Response
2.3.2. Drug Response Prediction
- (a)
- Gain of function in an oncogene;
- (b)
- CNV amplification in an oncogene;
- (c)
- Specific genetic alterations in an oncogene;
- (d)
- Genetic alterations in tumor suppressor genes.
- (i)
- The gene underlying the drug target shows a copy number increase;
- (ii)
- The drug targets a gene whose product shows a gain of function;
- (iii)
- A specific alteration with known drug effectiveness is present.
2.4. Ethics
3. Results
3.1. Targeted Therapy and Linked Genetic Targets
3.2. Genetic Alterations in ACC—The TCGA Dataset
3.3. Mutation Hotspots Based on the TCGA Data
3.4. CNV Co-Amplification Pairs Based on the TCGA Data
3.5. Potential Genomic Drug Response
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Drug/ ClinicalTrials.gov ID/Reference | Mechanism of Action | Setting | Primary Outcome | Study Design | Status |
---|---|---|---|---|---|
Cabozantinib NCT03612232 | VEGFR 1/2/3, KIT, NTRK2, FLT-3, AXL, RET, MET, and TEK. | Relapsed/refractory advanced or metastatic ACC (mitotane discontinued, serum concentration < 2 mg/L) | PFS at 4 months | Single-arm Phase II | Recruiting |
Cabozantinib NCT03370718 | Locally advanced or metastatic ACC (mitotane stopped for 1 month, serum concentration < 2 mg/L) | PFS at 4 months | Single-arm phase II | Active, not recruiting | |
Camrelizumab/Apatinib NCT04318730 | Camrelizumab: PD-1 receptor Apatinib: VEGF2, KIT, SRC | Second-line treatment of recurrent or metastatic adrenocortical carcinoma | ORR | Single-arm phase II | not yet recruiting |
IPI-549 (Eganelisib)/Nivolumab NCT02637531 | IPI-549: PIK3C Nivolumab: PD-1 receptor | ACC locally advanced or metastatic and other advanced and/or metastatic carcinoma or melanoma, excluding sarcoma | DLT, AE | Single Arm phase I/Ib | active, not recruiting |
Relacorilant/pembrolizumab NCT04373265 | Relacorilant: SGRM Pembrolizumab: PD-1 receptor | Locally advanced or metastatic ACC with glucocorticoid excess (mitotane level ≤ 4 mg/L) | ORR, dose-limiting toxicities | Phase Ib | recruiting |
Therapeutic vaccine (EO2401)/nivolumab NCT04187404 | Nivolumab: PD-1 receptor | ACC locally advanced or metastatic (also including pheochromocytoma or paraganglioma) | Safety | Phase I/II | recruiting |
ONC201 NCT03034200 | MAPK1 | Unresectable, recurrent, locally advanced, refractory, or metastatic neuroendocrine tumors including cholangiocarcinoma and ACC (age 14 and older) | CR, PR | Single-arm phase II | active not recruiting |
Nivolumab/ipilimumab NCT03333616 | Nivolumab: PD-1 receptor ipilimumab: CTLA-4 binding | Locally advanced or metastatic ACC (mitotane allowed for control or endocrine symptoms) and other rare genitourinary tumors | ORR | Single arm phase II | Recruiting |
Nivolumab/ipilimumab NCT02834013 | Relapsed/refractory advanced or metastatic ACC or other rare tumors | ORR | Single-arm, phase II | Recruiting | |
Pembrolizumab NCT02721732 | Pembrolizumab: PD-1 receptor | Relapsed/refractory advanced or metastatic ACC or other rare tumors | Non-progression at 27 weeks, adverse events | Single-arm phase II | active, not recruiting |
Pembrolizumab/lenvatinib NCT05036434 | Pembrolizumab: PD-1 receptor Lenvatinib: VEGFR, PDGFR, EGFR, RET, KIT | Advanced ACC after failure of platinum- and mitotane-based chemotherapy | ORR | single-arm phase II | Not yet recruiting |
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Share and Cite
Hescheler, D.A.; Hartmann, M.J.M.; Riemann, B.; Michel, M.; Bruns, C.J.; Alakus, H.; Chiapponi, C. Targeted Therapy for Adrenocortical Carcinoma: A Genomic-Based Search for Available and Emerging Options. Cancers 2022, 14, 2721. https://doi.org/10.3390/cancers14112721
Hescheler DA, Hartmann MJM, Riemann B, Michel M, Bruns CJ, Alakus H, Chiapponi C. Targeted Therapy for Adrenocortical Carcinoma: A Genomic-Based Search for Available and Emerging Options. Cancers. 2022; 14(11):2721. https://doi.org/10.3390/cancers14112721
Chicago/Turabian StyleHescheler, Daniel Alexander, Milan Janis Michael Hartmann, Burkhard Riemann, Maximilian Michel, Christiane Josephine Bruns, Hakan Alakus, and Costanza Chiapponi. 2022. "Targeted Therapy for Adrenocortical Carcinoma: A Genomic-Based Search for Available and Emerging Options" Cancers 14, no. 11: 2721. https://doi.org/10.3390/cancers14112721