bims-preonc 2024-09-15 papers

bims-preonc

Biomed News

on Precision oncology

Issue of 2024–09–15
twelve papers selected by
Ankita Daiya, OneCell Diagnostics Inc.

Radiogenomics: bridging the gap between imaging and genomics for precision oncology.
Optimized biomarker evaluation and molecular testing in the era of breast cancer precision medicine.
Genomic and molecular alterations associated with primary resistance to immune checkpoint inhibitors.
Serotonergic Drugs for the Treatment of Attention-Deficit/Hyperactivity Disorder: A Review of Past Development, Pitfalls and Failures, and a Look to the Future.
Exceptional Response to Pembrolizumab in HER2-Positive Gallbladder Carcinoma with High Tumor Mutational Burden.
Mutational Signatures in Colorectal Cancer: Translational Insights, Clinical Applications, and Limitations.
The Molecular and Immunological Landscape of Meningiomas.
The Potential of Circulating Cell-Free RNA in CNS Tumor Diagnosis and Monitoring: A Liquid Biopsy Approach.
Chemotactic signaling pathways in prostate cancer: Implications in the tumor microenvironment and as potential therapeutic targets.
Optimizing ctDNA: An Updated Review of a Promising Clinical Tool for the Management of Uveal Melanoma.
Oncologic Outcomes of Incidental Versus Biopsy-diagnosed Grade Group 1 Prostate Cancer: A Multi-institutional Study.
Olaparib combined with CDK12-IN-3 to promote genomic instability and cell death in ovarian cancer.

MedComm (2020). 2024 Sep;5(9): e722

Radiogenomics: bridging the gap between imaging and genomics for precision oncology.

Wenle He, Wenhui Huang, Lu Zhang, Xuewei Wu, Shuixing Zhang, Bin Zhang.

  Genomics allows the tracing of origin and evolution of cancer at molecular scale and underpin modern cancer diagnosis and treatment systems. Yet, molecular biomarker-guided clinical decision-making encounters major challenges in the realm of individualized medicine, consisting of the invasiveness of procedures and the sampling errors due to high tumor heterogeneity. By contrast, medical imaging enables noninvasive and global characterization of tumors at a low cost. In recent years, radiomics has overcomes the limitations of human visual evaluation by high-throughput quantitative analysis, enabling the comprehensive utilization of the vast amount of information underlying radiological images. The cross-scale integration of radiomics and genomics (hereafter radiogenomics) has the enormous potential to enhance cancer decoding and act as a catalyst for digital precision medicine. Herein, we provide a comprehensive overview of the current framework and potential clinical applications of radiogenomics in patient care. We also highlight recent research advances to illustrate how radiogenomics can address common clinical problems in solid tumors such as breast cancer, lung cancer, and glioma. Finally, we analyze existing literature to outline challenges and propose solutions, while also identifying future research pathways. We believe that the perspectives shared in this survey will provide a valuable guide for researchers in the realm of radiogenomics aiming to advance precision oncology.

Keywords:  artificial intelligence; oncology; precision medicine; radiogenomics; radiomics

DOI:  https://doi.org/10.1002/mco2.722
Biotech Histochem. 2024 Sep 11. 1-13

Optimized biomarker evaluation and molecular testing in the era of breast cancer precision medicine.

David G Hicks, Bradley M Turner.

  Ground breaking advances in medicine, driven in part by major technologic developments in molecular biology have led us to a new model for cancer care that has been termed personalized, or precision medicine. Precision medicine is a model for making medical decisions that employs an innovative clinical approach and advanced tumor testing methods that are tailored to understanding an individual patient's tumor biology and the molecular drivers of their disease. This medical model includes a combination of diagnostic testing and specific treatment options that can be offered to patients at presentation and in theory throughout the course of their disease as new mutations arise with the development of disease recurrence. Although the precision medicine model offers incredible potential to transform cancer care, these advances are only meaningful when they reach the correct patients. The evolving paradigm of precision medicine is changing the practice of pathology, and the pathology community needs to be mindful of these changes because every tissue specimen represents a patient's life, and those patients are depending on the pathology community to handle their tissue correctly. The diagnostic tests performed in the pathology laboratory for precision medicine are increasingly complex, and pathologists along with the entire laboratory and clinical communities need to take steps to ensure that the right diagnosis is given to the right patient to inform the right treatment options, at the right time, along every step of the continuum of care for cancer patients. While hormone receptors and human epidermal growth factor receptor 2 (HER2) overexpression and/or amplification have been the mainstay for risk-stratification, and treatment decision making in breast cancer since the early 2000's, the seminal work on gene expression by Perou and colleagues in the early 2000's opened the door for molecular testing in the prognostic and predictive assessment of breast cancer. Molecular testing is now part of the standard of care in the precision medicine model for breast cancer care. In this article, the reader will gain a better understanding of how the lack of standardization of pre-analytic factors has the potential to negatively impact the quality of the tissue specimen for downstream biomarker and molecular testing, which ultimately can negatively affect patient care. The reader will also gain insight into the current climate surrounding molecular testing in breast cancer.

Keywords:  Biomarker; breast cancer; molecular testing; precision medicine

DOI:  https://doi.org/10.1080/10520295.2024.2390179
Cancer Immunol Immunother. 2024 Sep 13. 73(11): 234

Genomic and molecular alterations associated with primary resistance to immune checkpoint inhibitors.

Jyoti Malhotra, Subhajyoti De, Kim Nguyen, Percy Lee, Victoria Villaflor.

  The clinical response to immune checkpoint inhibitors may vary by tumor type and many tumors present with either primary or acquired resistance to immunotherapy. Improved understanding of the molecular and immunologic mechanisms underlying immunotherapy resistance is essential for developing biomarkers and for guiding the optimum approach to selecting treatment regimens and sequencing. This is increasingly important for tumors with primary resistance as effective biomarkers in this setting can guide clinicians about appropriate treatment regimen selection in the first-line setting. Multiple potential biological mechanisms of primary resistance have been proposed but most are yet to be validated in prospective clinical cohorts. Individual biomarkers have poor specificity and sensitivity, and the development of validated and integrated predictive models may guide which patient will benefit from monotherapy versus combination therapy. In this review, we discuss the emerging data identifying the molecular mechanisms of primary resistance to immunotherapy and explore potential therapeutic strategies to target these.

Keywords:  Genomic; Immunotherapy; Molecular; Primary resistance

DOI:  https://doi.org/10.1007/s00262-024-03825-z
Psychopharmacol Bull. 2024 Aug 19. 54(4): 45-80

Serotonergic Drugs for the Treatment of Attention-Deficit/Hyperactivity Disorder: A Review of Past Development, Pitfalls and Failures, and a Look to the Future.

Craig Chepke, Elizabeth Brunner, Andrew J Cutler.

Serotonin has been implicated in the neurobiology of attention-deficit/hyperactivity disorder (ADHD) due to its association with impulsivity, attention, and emotional regulation. Many compounds with serotonergic properties have been evaluated in ADHD, but few have been approved by regulatory authorities. Utilizing a search of public databases, we identified interventions studied in ADHD. Prescribing information and peer-reviewed and gray literature helped us to determine which compounds had an underlying mechanism of action associated with changing serotonin levels. Of the 24 compounds that met the search criteria, 16 had either failed clinical studies in an ADHD population or had been discontinued from future development. The available evidence was assessed to identify the developmental history of drugs with serotonergic activity and the outlook for new ADHD drug candidates targeting serotonin. Several treatment candidates floundered due to an inability to balance effectiveness with safety, underscoring the potential importance of potency, and selectivity. Ongoing drug development includes compounds with multimodal mechanisms of action targeting neurotransmission across serotonin, norepinephrine, and dopamine pathways; it appears likely that treatment which balances competing and complementary monoamine effects may provide improved outcomes for patients. It is hoped that continuing research into ADHD treatment will produce new therapeutic options targeting the serotonergic system, which can positively impact a wide range of symptoms, including mood, anxiety, and sleep as well as attention and hyperactivity.

Keywords: adverse effects; attention deficit disorder with hyperactivity; drug development; pharmacology; serotonin; serotonin agents
J Gastrointest Cancer. 2024 Sep 10.

Exceptional Response to Pembrolizumab in HER2-Positive Gallbladder Carcinoma with High Tumor Mutational Burden.

Akinori Sasaki, Satoru Nakajima, Yasuaki Motomura.

   PURPOSE: Patients with advanced cholangiocarcinoma, including gallbladder cancer, typically have a poor prognosis owing to limited effective chemotherapy options. The field of genotype-directed therapy in patients with cholangiocarcinoma is advancing. However, limited clinical data are currently available to evaluate the efficacy of molecularly targeted therapy.
METHODS: Herein, we report the case of a 67-year-old man diagnosed with human epidermal growth factor receptor-2 (HER2)-positive and tumor mutation burden-high (TMB-H) cholangiocarcinoma. The HER2-positive and TMB-H characteristics were identified using comprehensive genomic profiling after showing resistance to gemcitabine and S-1 therapy. In the absence of clinical trials for HER2-positive cancer at that time, the patient was treated with pembrolizumab, which is used for TMB-H solid tumors in clinical practice.
RESULTS: After receiving pembrolizumab, the patient experienced significant shrinkage in the primary tumor and liver metastases. Thus far, the patient has been receiving pembrolizumab for approximately 10 months.
CONCLUSION: To our knowledge, this is the first report showing the efficacy of pembrolizumab in a patient with cholangiocarcinoma harboring both HER2-positive and TMB-H.

Keywords:  Cholangiocarcinoma; Gallbladder carcinoma; HER2-positive; Pembrolizumab; Tumor mutational burden-high

DOI:  https://doi.org/10.1007/s12029-024-01112-9
Cancers (Basel). 2024 Aug 24. pii: 2956. [Epub ahead of print]16(17):

Mutational Signatures in Colorectal Cancer: Translational Insights, Clinical Applications, and Limitations.

Giovanni Crisafulli.

  A multitude of exogenous and endogenous processes have the potential to result in DNA damage. While the repair mechanisms are typically capable of correcting this damage, errors in the repair process can result in mutations. The findings of research conducted in 2012 indicate that mutations do not occur randomly but rather follow specific patterns that can be attributed to known or inferred mutational processes. The process of mutational signature analysis allows for the inference of the predominant mutational process for a given cancer sample, with significant potential for clinical applications. A deeper comprehension of these mutational signatures in CRC could facilitate enhanced prevention strategies, facilitate the comprehension of genotoxic drug activity, predict responses to personalized treatments, and, in the future, inform the development of targeted therapies in the context of precision oncology. The efforts of numerous researchers have led to the identification of several mutational signatures, which can be categorized into different mutational signature references. In CRC, distinct mutational signatures are identified as correlating with mismatch repair deficiency, polymerase mutations, and chemotherapy treatment. In this context, a mutational signature analysis offers considerable potential for enhancing minimal residual disease (MRD) tests in stage II (high-risk) and stage III CRC post-surgery, stratifying CRC based on the impacts of genetic and epigenetic alterations for precision oncology, identifying potential therapeutic vulnerabilities, and evaluating drug efficacy and guiding therapy, as illustrated in a proof-of-concept clinical trial.

Keywords:  bioinformatics; clinical application; clinical trial; colorectal cancers; computational biology; genetics; genomics; mutational signatures; oncology; precision oncology

DOI:  https://doi.org/10.3390/cancers16172956
Int J Mol Sci. 2024 Sep 05. pii: 9631. [Epub ahead of print]25(17):

The Molecular and Immunological Landscape of Meningiomas.

Catharina Lotsch, Rolf Warta, Christel Herold-Mende.

  Meningiomas are the most common primary intracranial tumors in adults and typically have a slow-growing and benign nature. However, there is also a substantial subset of meningiomas that shows aggressive clinical behavior and is refractory to standard treatment modalities, which are still limited to surgery and/or radiotherapy. Despite intensive research, no systemic treatment options are yet available in the clinic for these challenging tumors, resulting in poor patient outcome. Intensive research on the molecular pathogenesis of meningiomas has led to improved diagnostic tools, but so far there is no standardized implementation for the molecular profiling of these tumors for clinical practice. Recent research advances have also focused on the immunophenotyping of meningiomas, leading to several clinical trials examining the use of immune checkpoint blockade therapy in patients with clinically aggressive subtypes. In this review, we aim to summarize the current knowledge on the molecular and immunological landscape of meningiomas in detail and provide current and progressive ideas for future directions.

Keywords:  DNA methylation; brain tumor diagnostics; immunobiology; immunotherapy; infiltrating immune cells; meningioma; meningioma prognosis; molecular profiling

DOI:  https://doi.org/10.3390/ijms25179631
Crit Rev Oncol Hematol. 2024 Sep 07. pii: S1040-8428(24)00247-6. [Epub ahead of print] 104504

The Potential of Circulating Cell-Free RNA in CNS Tumor Diagnosis and Monitoring: A Liquid Biopsy Approach.

Carlos Pilotto Heming, Veronica Aran.

  Early detection of malignancies, through regular cancer screening, has already proven to have potential to increase survival rates. Yet current screening methods rely on invasive, expensive tissue sampling that has hampered widespread use. Liquid biopsy is noninvasive and represents a potential approach to precision oncology, based on molecular profiling of body fluids. Among these, circulating cell-free RNA (cfRNA) has gained attention due to its diverse composition and potential as a sensitive biomarker. This review provides an overview of the processes of cfRNA delivery into the bloodstream and the role of cfRNA detection in the diagnosis of central nervous system (CNS) tumors. Different types of cfRNAs such as microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) have been recognized as potential biomarkers in CNS tumors. These molecules exhibit differential expression patterns in the plasma, cerebrospinalfluid (CSF) and urine of patients with CNS tumors, providing information for diagnosing the disease, predicting outcomes, and assessing treatment effectiveness. Few clinical trials are currently exploring the use of liquid biopsy for detecting and monitoring CNS tumors. Despite obstacles like sample standardization and data analysis, cfRNA shows promise as a tool in the diagnosis and management of CNS tumors, offering opportunities for early detection, personalized therapy, and improved patient outcomes.

Keywords:  Liquid biopsy; brain tumor; cancer biomarkers; cell-free RNA; central nervous system

DOI:  https://doi.org/10.1016/j.critrevonc.2024.104504
Int Rev Cell Mol Biol. 2024 ;pii: S1937-6448(24)00048-0. [Epub ahead of print]388 162-205

Chemotactic signaling pathways in prostate cancer: Implications in the tumor microenvironment and as potential therapeutic targets.

Zoila A Lopez-Bujanda, Shawn H Hadavi, Vicenç Ruiz De Porras, Eva Martínez-Balibrea, Matthew C Dallos.

  Prostate cancer (PCa) stands as a significant global health concern, ranking among the leading causes of cancer deaths in men. While there are several treatment modalities for localized PCa, metastatic castration-resistant PCa (mCRPC) remains incurable. Despite therapeutic advancements showing promise in mCRPC, their impact on overall survival has been limited. This chapter explores the process by which tumors form, reviews our current understanding of PCa progression to mCRPC, and addresses the challenges of boosting anti-tumor immune responses in these tumors. It specifically discusses how chemotactic signaling affects the tumor microenvironment and its role in immune evasion and cancer progression. The chapter further examines the rationale of directly or indirectly targeting these pathways as adjuvant therapies for mCRPC, highlighting recent pre-clinical and clinical studies currently underway. The discussion emphasizes the potential of targeting specific chemokines and chemokine receptors as combination therapies with mainstream treatments for PCa and mCRPC to maximize long-term survival for this deadly disease.

Keywords:  Anti-tumor immune response; Chemo-sensitivity; Chemo-sensitizers; Chemokine receptors; Chemotactic modulation; Chemotactic signaling pathways; Immunogenic; Immunosuppressive; Prostate cancer (PCa); Tumor microenvironment (TME)

DOI:  https://doi.org/10.1016/bs.ircmb.2024.03.008
Cancers (Basel). 2024 Sep 01. pii: 3053. [Epub ahead of print]16(17):

Optimizing ctDNA: An Updated Review of a Promising Clinical Tool for the Management of Uveal Melanoma.

Mar Varela, Sergi Villatoro, Daniel Lorenzo, Josep Maria Piulats, Josep Maria Caminal.

  Uveal melanoma (UM) is the most common primary malignant intraocular tumor in adults. Distant metastasis is common, affecting around 50% of patients. Prognostic accuracy relies on molecular characterization of tumor tissue. In these patients, however, conventional biopsy can be challenging due to the difficulty of obtaining sufficient tissue for the analysis due to the small tumor size and/or post-brachytherapy shrinkage. An alternative approach is liquid biopsy, a non-invasive technique that allows for real-time monitoring of tumor dynamics. Liquid biopsy plays an increasingly prominent role in precision medicine, providing valuable information on the molecular profile of the tumor and treatment response. Liquid biopsy can facilitate early detection and can be used to monitor progression and recurrence. ctDNA-based tests are particularly promising due to their ease of integration into clinical practice. In this review, we discuss the application of ctDNA in liquid biopsies for UM. More specifically, we explore the emerging technologies in this field and the advantages and disadvantages of using different bodily fluids for liquid biopsy. Finally, we discuss the current barriers to routine clinical use of this technique.

Keywords:  circulating tumor DNA; liquid biopsy; molecular techniques; oncology; precision medicine; uveal melanoma

DOI:  https://doi.org/10.3390/cancers16173053
Eur Urol Open Sci. 2024 Oct;68 10-17

Oncologic Outcomes of Incidental Versus Biopsy-diagnosed Grade Group 1 Prostate Cancer: A Multi-institutional Study.

EAU-YAU Prostate Cancer Working Group

   Background and objective: Patients diagnosed with grade group (GG) 1 prostate cancer (PCa) following treatment for benign disease ("incidental" PCa) are typically managed with active surveillance (AS). It is not known how their outcomes compare with those observed in patients diagnosed with GG1 on biopsy. We aimed at determining whether long-term oncologic outcomes of AS for patients with GG1 PCa differ according to the type of diagnosis: incidental versus biopsy detected.
Methods: A retrospective, multi-institutional analysis of PCa patients with GG1 on AS at eight institutions was conducted. Competing risk analyses estimated the incidence of metastases, PCa mortality, and conversion to treatment. As a secondary analysis, we estimated the risk of GG ≥2 on the first follow-up biopsy according to the type of initial diagnosis.
Key findings and limitations: A total of 213 versus 1900 patients with incidental versus biopsy-diagnosed GG1 were identified. Patients with incidental cancers were followed with repeated biopsies and multiparametric magnetic resonance imaging less frequently than those diagnosed on biopsy. The 10-yr incidence of treatment was 22% for incidental cancers versus 53% for biopsy (subdistribution hazard ratio [sHR] 0.34, 95% confidence interval [CI] 0.26-0.46, p < 0.001). Distant metastases developed in one patient with incidental cancer versus 17 diagnosed on biopsy and were diagnosed with molecular imaging in 13 (72%) patients. The 10-yr incidence of metastases was 0.8% for patients with incidental PCa and 2% for those diagnosed on biopsy (sHR 0.35, 95% CI 0.05-2.54, p = 0.3). The risk of GG ≥2 on the first follow-up biopsy was low if the initial diagnosis was incidental (7% vs 22%, p < 0.001).
Conclusions and clinical implications: Patients with GG1 incidental PCa should be evaluated further to exclude aggressive disease, preferably with a biopsy. If no cancer is found on biopsy, then they should receive the same follow-up of a patient with a negative biopsy. Further research should confirm whether imaging and biopsies can be avoided if postoperative prostate-specific antigen is low (<1-2 ng/ml).
Patient summary: We compared the outcomes of patients with low-grade prostate cancer on active surveillance according to the type of their initial diagnosis. Patients who have low-grade cancer diagnosed on a procedure to relieve urinary symptoms (incidental prostate cancer) are followed less intensively and undergo curative-intended treatment less frequently. We also found that patients with incidental prostate cancer are more likely to have no cancer on their first follow-up biopsy than patients who have low-grade cancer initially diagnosed on a biopsy. These patients have a more favorable prognosis than their biopsy-detected counterparts and should be managed the same way as patients with negative biopsies if they undergo a subsequent biopsy that shows no cancer.

Keywords:  Active surveillance; Incidental prostate cancer; Metastases; Surveillance biopsies

DOI:  https://doi.org/10.1016/j.euros.2024.08.004
Int J Biol Sci. 2024 ;20(11): 4513-4531

Olaparib combined with CDK12-IN-3 to promote genomic instability and cell death in ovarian cancer.

Jianqiang Liang, Xuan Zhou, Lin Yuan, Tian Chen, Yicong Wan, Yi Jiang, Huangyang Meng, Mengting Xu, Lin Zhang, Wenjun Cheng.

  Large-scale phase III clinical trials of Olaparib have revealed benefits for ovarian cancer patients with BRCA gene mutations or homologous recombination deficiency (HRD). However, fewer than 50% of ovarian cancer patients have both BRCA mutations and HRD. Therefore, improving the effect of Olaparib in HR-proficient patients is of great clinical value. Here, a combination strategy comprising Olaparib and CDK12-IN-3 effectively inhibited the growth of HR-proficient ovarian cancer in cell line, patient-derived organoid (PDO), and mouse xenograft models. Furthermore, the combination strategy induced severe DNA double-strand break (DSB) formation, increased NHEJ activity in the G2 phase, and reduced HR activity in cancer cells. Mechanistically, the combination treatment impaired Ku80 poly(ADP-ribosyl)ation (PARylation) and phosphorylation, resulting in PARP1-Ku80 complex dissociation. After dissociation, Ku80 occupancy at DSBs and the resulting Ku80-primed NHEJ activity were increased. Owing to Ku80-mediated DNA end protection, MRE11 and Rad51 foci formation was inhibited after the combination treatment, suggesting that this treatment suppressed HR activity. Intriguingly, the combination strategy expedited cGAS nuclear relocalization, further suppressing HR and, conversely, increasing genomic instability. Moreover, the inhibitory effect on cell survival persisted after drug withdrawal. These findings provide a rationale for the clinical application of CDK12-IN-3 in combination with Olaparib.

Keywords:  CDK12i; HR; NHEJ; Olaparib; ovarian cancer

DOI:  https://doi.org/10.7150/ijbs.94568