In recent years, several new biomarkers supplementing the role of prostate-specific antigen (PSA) have become available for men with prostate cancer. Although widely used in an
manner, the role of ...PSA in screening asymptomatic men for prostate cancer is controversial. Several expert panels, however, have recently recommended limited PSA screening following informed consent in average-risk men, aged 55–69 years. As a screening test for prostate cancer however, PSA has limited specificity and leads to overdiagnosis which in turn results in overtreatment. To increase specificity and reduce the number of unnecessary biopsies, biomarkers such as percent free PSA, prostate health index (PHI) or the 4K score may be used, while Progensa PCA3 may be measured to reduce the number of repeat biopsies in men with a previously negative biopsy. In addition to its role in screening, PSA is also widely used in the management of patients with diagnosed prostate cancer such as in surveillance following diagnosis, monitoring response to therapy and in combination with both clinical and histological criteria in risk stratification for recurrence. For determining aggressiveness and predicting outcome, especially in low- or intermediate-risk men, tissue-based multigene tests such as Decipher, Oncotype DX (Prostate), Prolaris and ProMark, may be used. Emerging therapy predictive biomarkers include AR-V7 for predicting lack of response to specific anti-androgens (enzalutamide, abiraterone), BRAC1/2 mutations for predicting benefit from PARP inhibitor and PORTOS for predicting benefit from radiotherapy. With the increased availability of multiple biomarkers, personalised treatment for men with prostate cancer is finally on the horizon.
Immunotherapy, especially the use of immune checkpoint inhibitors, has revolutionized the management of several different cancer types in recent years. However, for most types of cancer, only a ...minority of patients experience a durable response. Furthermore, administration of immunotherapy can result in serious adverse reactions. Thus, for the most efficient and effective use of immunotherapy, accurate predictive biomarkers that have undergone analytical and clinical validation are necessary.
Among the most widely investigated predictive biomarkers for immunotherapy are programmed death-ligand 1 (PD-L1), microsatellite instability/defective mismatch repair (MSI/dMMR), and tumor mutational burden (TMB). MSI/dMMR is approved for clinical use irrespective of the tumor type, whereas PD-L1 is approved only for use in certain cancer types (e.g., for predicting response to first-line pembrolizumab monotherapy in non-small cell lung cancer). Although not yet approved for clinical use, TMB has been shown to predict response to several different forms of immunotherapy and across multiple cancer types. Less widely investigated predictive biomarkers for immunotherapy include tumor-infiltrating CD8
lymphocytes and specific gene signatures. Despite being widely investigated, assays for MSI/dMMR, PD-L1, and TMB lack standardization and are still evolving. An urgent focus of future research should be the optimization and standardization of method for determining these biomarkers.
Biomarkers for predicting response to immunotherapy are paving the way for personalized treatment for patients with diverse cancer types. However, standardization of the available biomarker assays is an urgent requirement.
Following a diagnosis of breast cancer, the most immediate challenges in patient management are the determination of prognosis and identification of the most appropriate adjuvant systemic therapy. ...Determining prognosis can best be addressed with a combination of traditional clinicopathological prognostic factors, biomarkers such as HER2/neu and specific multigene genes tests. Amongst the best validated prognostic multigene tests are uPA/PAI1, Oncotype DX and MammaPrint. Oncotype DX and MammaPrint, may be used for predicting outcome and aiding adjunct therapy decision making in patients with ER-positive, HER2-negative breast cancers that are either lymph node-negative or node positive (1–3 metastatic nodes), while uPA/PAI-1 may be similarly used in ER-positive, lymph node-negative patients. For selecting likely response to endocrine therapy, both estrogen receptors (ER) and progesterone receptors (PR) should be measured. On the other hand, for identifying likely response to anti-HER2 therapy, determination of HER2 gene amplification or overexpression is necessary. To identify new prognostic and predictive biomarkers for breast cancer, current research is focusing on tumor and circulating DNA (ctDNA) and RNA (e.g., micro RNAs) and circulating tumor cells. A promising ctDNA biomarker is the mutational status of ER (ESR1) for predicting the emergence of resistance to aromatase inhibitors. Challenges for future research include the identification of biomarkers for predicting response to radiotherapy and specific forms of chemotherapy.
RAS, TP53 (p53) and MYC are among the most frequently altered driver genes in cancer. Thus, RAS is the most frequently mutated oncogene, MYC the most frequently amplified gene and TP53 the most ...frequently mutated tumor suppressor gene and overall the most frequently mutated gene in cancer. Theoretically, therefore, these genes are highly attractive targets for cancer treatment. However, as the protein products of each of these genes lack an accessible hydrophobic pocket into which low molecular weight compounds might bind with high affinity, they have proved difficult to target and have traditionally been referred to as “undruggable.” Despite this branding, several low molecular weight compounds targeting each of these proteins have recently been reported to have anticancer activity in preclinical models. Indeed, several drugs inhibiting mutant KRAS, MYC overexpression or reactivating mutant p53 have undergone or are currently undergoing clinical trials. For targeting mutant KRAS and reactivating mutant p53, trials have progressed to a Phase III stage, that is, the mutant‐p53 reactivating drug, APR‐246 is currently being investigated in patients with myelodysplastic syndrome (MDS) and the RAS inhibitor, rigosertib is also undergoing evaluation in patients with MDS. Although there appears to be no directly acting MYC inhibitor currently being tested in a clinical trial, an anti‐MYC compound, known as OmoMYC has been extensively validated in multiple preclinical models and is being developed for clinical evaluation. Based on current evidence, the traditional perception of RAS, p53 and MYC as being “undruggable” would appear to be coming to an end.
MYC as a target for cancer treatment Duffy, Michael J.; O'Grady, Shane; Tang, Minhong ...
Cancer treatment reviews,
March 2021, 2021-Mar, 2021-03-00, 20210301, Letnik:
94
Journal Article
Recenzirano
Odprti dostop
•The MYC family of proto-oncogenes are frequently altered in human cancers and represent an attractive target for therapy.•Therapeutic targeting of MYC has previously been hampered by difficulties in ...drug development.•Newly developed agents can target MYC through multiple mechanisms, including inhibition of MAX binding and blocking MYC-DNA interaction.•Some of these agents are now progressing through clinical trials.
The MYC gene which consists of 3 paralogs, C-MYC, N-MYC and L-MYC, is one of the most frequently deregulated driver genes in human cancer. Because of its high prevalence of deregulation and its causal role in cancer formation, maintenance and progression, targeting MYC is theoretically an attractive strategy for treating cancer. As a potential anticancer target, MYC was traditionally regarded as undruggable due to the absence of a suitable pocket for high-affinity binding by low molecular weight inhibitors. In recent years however, several compounds that directly or indirectly inhibit MYC have been shown to have anticancer activity in preclinical tumor models. Amongst the most detailed investigated strategies for targeting MYC are inhibition of its binding to its obligate interaction partner MAX, prevention of MYC expression and blocking of genes exhibiting synthetic lethality with overexpression of MYC. One of the most extensively investigated MYC inhibitors is a peptide/mini-protein known as OmoMYC. OmoMYC, which acts by blocking the binding of all 3 forms of MYC to their target promoters, has been shown to exhibit anticancer activity in a diverse range of preclinical models, with minimal side effects. Based on its broad efficacy and limited toxicity, OmoMYC is currently being developed for evaluation in clinical trials. Although no compound directly targeting MYC has yet progressed to clinical testing, APTO-253, which partly acts by decreasing expression of MYC, is currently undergoing a phase I clinical trial in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome.
Mutant p53 as a target for cancer treatment Duffy, Michael J.; Synnott, Naoise C.; Crown, John
European journal of cancer (1990),
September 2017, 2017-09-00, 20170901, Letnik:
83
Journal Article
Recenzirano
TP53 (p53) is the single most frequently altered gene in human cancers, with mutations being present in approximately 50% of all invasive tumours. However, in some of the most difficult-to-treat ...cancers such as high-grade serous ovarian cancers, triple-negative breast cancers, oesophageal cancers, small-cell lung cancers and squamous cell lung cancers, p53 is mutated in at least 80% of samples. Clearly, therefore, mutant p53 protein is an important candidate target against which new anticancer treatments could be developed. Although traditionally regarded as undruggable, several compounds such as p53 reactivation and induction of massive apoptosis-1 (PRIMA-1), a methylated derivative and structural analogue of PRIMA-1, i.e. APR-246, 2-sulfonylpyrimidines such as PK11007, pyrazoles such as PK7088, zinc metallochaperone-1 (ZMC1), a third generation thiosemicarbazone developed by Critical Outcome Techonologies Inc. (COTI-2) as well as specific peptides have recently been reported to reactive mutant p53 protein by converting it to a form exhibiting wild-type properties. Consistent with the reactivation of mutant p53, these compounds have been shown to exhibit anticancer activity in preclinical models expressing mutant p53. To date, two of these compounds, i.e. APR-246 and COTI-2 have progressed to clinical trials. A phase I/IIa clinical trial with APR-246 reported no major adverse effect. Currently, APR-246 is undergoing a phase Ib/II trial in patients with advanced serous ovarian cancer, while COTI-2 is being evaluated in a phase I trial in patients with advanced gynaecological cancers. It remains to be shown however, whether any mutant p53 reactivating compound has efficacy for the treatment of human cancer.
•Summary of p53 mutations occurring in cancer.•Proof of concept of targeting mutant p53 in cancer.•Review of the current drugs available to target p53 and the stages in their preclinical/clinical development.
Targeting p53 for the treatment of cancer Duffy, Michael J.; Synnott, Naoise C.; O’Grady, Shane ...
Seminars in cancer biology,
February 2022, 2022-02-00, 20220201, Letnik:
79
Journal Article
Recenzirano
Odprti dostop
Dysfunction of the TP53 (p53) gene occurs in most if not all human malignancies. Two principal mechanisms are responsible for this dysfunction; mutation and downregulation of wild-type p53 mediated ...by MDM2/MDM4. Because of its almost universal inactivation in malignancy, p53 is a highly attractive target for the development of new anticancer drugs. Although multiple strategies have been investigated for targeting dysfunctional p53 for cancer treatment, only 2 of these have so far yielded compounds for testing in clinical trials. These strategies include the identification of compounds for reactivating the mutant form of p53 back to its wild-type form and compounds for inhibiting the interaction between wild-type p53 and MDM2/MDM4. Currently, multiple p53-MDM2/MDM4 antagonists are undergoing clinical trials, the most advanced being idasanutlin which is currently undergoing testing in a phase III clinical trial in patients with relapsed or refractory acute myeloid leukemia. Two mutant p53-reactivating compounds have progressed to clinical trials, i.e., APR-246 and COTI-2. Although promising data has emerged from the testing of both MDM2/MDM4 inhibitors and mutant p53 reactivating compounds in preclinical models, it is still unclear if these agents have clinical efficacy. However, should any of the compounds currently being evaluated in clinical trials be shown to have efficacy, it is likely to usher in a new era in cancer treatment, especially as p53 dysfunction is so prevalent in human cancers.
Objective
The aim of this article is to discuss mutant p53 as a possible therapeutic target and biomarker for breast cancer.
Results
TP53 (p53) is the most frequently mutated gene in invasive breast ...cancer. Although mutated in 30–35% of all cases, p53 is mutated in approximately 80% of triple-negative (TN) tumors (i.e., tumors negative for ER, PR, and HER2). Because of this high prevalence, mutated p53 is both a potential biomarker and therapeutic target for patients with breast cancer, especially for those with the TN subtype. Although several retrospective studies have investigated a potential prognostic and therapy predictive role for mutant p53 in breast cancer, the results to date are mixed. Thus, at present, mutant p53 cannot be recommended as a prognostic or therapy predictive biomarker in breast cancer. In contrast to the multiple reports on a potential biomarker role, few studies had until recently, investigated mutant p53 as a potential target for breast cancer treatment. In the last decade, however, several compounds have become available which can reactivate mutant p53 protein and convert it to a conformation with wild-type properties. Some of these compounds, especially PRIMA-1, APR-246 PK11007, and COTI-2, have been found to exhibit anticancer activity in preclinical models of breast cancer.
Conclusion
Since p53 is mutated in the vast majority of TN breast cancers, compounds such as APR-246, PK11007, and COTI-2 are potential treatments for patients with this subform of the disease. Further research is necessary to identify a potential biomarker role for mutant p53 in breast cancer.
Protein-based biomarkers are widely used in monitoring patients with diagnosed cancer. These biomarkers however, lack specificity for cancer and have poor sensitivity in detecting early recurrences ...and monitoring therapy effectiveness. Emerging data suggest that the use of circulating tumor DNA (ctDNA) has several advantages over standard biomarkers.
Following curative-intent surgery for cancer, the presence of ctDNA is highly predictive of early disease recurrence, while in metastatic cancer an early decline in ctDNA following the initiation of treatment is predictive of good outcome. Compared with protein biomarkers, ctDNA provides greater cancer specificity and sensitivity for detecting early recurrent/metastatic disease. Thus, in patients with surgically resected colorectal cancer, multiple studies have shown that ctDNA is superior to carcinoembryonic antigen (CEA) in detecting residual disease and early recurrence. Similarly, in breast cancer, ctDNA was shown to be more accurate than carbohydrate antigen 15-3 (CA 15-3) in detecting early recurrences. Other advantages of ctDNA over protein biomarkers in monitoring cancer patients include a shorter half-life in plasma and an ability to predict likely response to specific therapies and identify mechanisms of therapy resistance. However, in contrast to proteins, ctDNA biomarkers are more expensive to measure, less widely available, and have longer turnaround times for reporting. Furthermore, ctDNA assays are less well standardized.
Because of their advantages, it is likely that ctDNA measurements will enter clinical use in the future, where they will complement existing biomarkers and imaging in managing patients with cancer. Hopefully, these combined approaches will lead to a better outcome for patients.
Tumor markers are playing an increasingly important role in cancer detection and management. These laboratory-based tests are potentially useful in screening for early malignancy, aiding cancer ...diagnosis, determining prognosis, surveillance following curative surgery for cancer, up front predicting drug response or resistance, and monitoring therapy in advanced disease. Clinically useful markers include fecal occult blood testing in screening for early colorectal cancer, carcinoembryonic antigen in the management of patients with colorectal cancer, both α-fetoprotein and human chorionic gonadotrophin in the management of patients with non-seminomatous germ cell tumors, CA 125 for monitoring therapy in patients with ovarian cancer, estrogen receptors for predicting response to hormone therapy in breast cancer, human epidermal growth factor receptor 2 for the identification of women with breast cancer likely to respond to trastuzumab (Herceptin) and KRAS mutational status for identifying patients with advanced colorectal cancer likely to benefit from treatment with the anti-epidermal growth factor receptor antibodies, cetuximab and panitumumab. Although widely used, the value of prostate-specific antigen screening in reducing mortality from prostate cancer is unclear.
PDF
