Precision Cancer Medicine Research Articles

Oncogenic Proteomics Approaches for Translational Research and HIV-Associated Malignancy Mechanisms.

Recent advances in the field of proteomics have allowed extensive insights into the molecular regulations of the cell proteome. Specifically, this allows researchers to dissect a multitude of signaling arrays while targeting for the discovery of novel protein signatures. These approaches based on data mining are becoming increasingly powerful for identifying both potential disease mechanisms as well as indicators for disease progression and overall survival predictive and prognostic molecular markers for cancer. Furthermore, mass spectrometry (MS) integrations satisfy the ongoing demand for in-depth biomarker validation. For the purpose of this review, we will highlight the current developments based on MS sensitivity, to place quantitative proteomics into clinical settings and provide a perspective to integrate proteomics data for future applications in cancer precision medicine. We will also discuss malignancies associated with oncogenic viruses such as Acquire Immunodeficiency Syndrome (AIDS) and suggest novel mechanisms behind this phenomenon. Human Immunodeficiency Virus type-1 (HIV-1) proteins are known to be oncogenic per se, to induce oxidative and endoplasmic reticulum stresses, and to be released from the infected or expressing cells. HIV-1 proteins can act alone or in collaboration with other known oncoproteins, which cause the bulk of malignancies in people living with HIV-1 on ART.

Precision medicine: Transforming healthcare through personalized treatment and genomic insights

ABSTRACT This article explores the paradigm shift brought about by precision medicine in healthcare. It provides an overview of the field’s historical background, key milestones, advantages, real-life examples, major companies, products, challenges, and future prospects. Readers can expect to gain insights into the emergence of precision medicine, its impact on diagnosis and treatment, and its potential to revolutionize healthcare. The article highlights significant achievements such as the completion of the Human Genome Project, the development of targeted therapies, and the role of precision medicine in cancer, cardiovascular disease, rare diseases, infectious diseases, and mental health disorders. It also discusses prominent companies and their contributions to precision medicine. However, challenges such as the cost of genetic testing and the need for robust data infrastructure are explored. The importance of collaboration, education, awareness, regulation, and standardization is emphasized. By the end, readers will have a comprehensive understanding of precision medicine’s promise, its current state, and the steps needed for its widespread adoption, enabling them to grasp its potential impact on patient outcomes and health-care systems.

Parents' expectations, preferences, and recall of germline findings in a childhood cancer precision medicine trial.

Germline genome sequencing in childhood cancer precision medicine trials may reveal pathogenic or likely pathogenic variants in cancer predisposition genes in more than 10% of children. These findings can have implications for diagnosis, treatment, and the child's and family's future cancer risk. Understanding parents' perspectives of germline genome sequencing is critical to successful clinical implementation. A total of 182 parents of 144 children (<18 years of age) with poor-prognosis cancers enrolled in the Precision Medicine for Children with Cancer trial completed a questionnaire at enrollment and after the return of their child's results, including clinically relevant germline findings (received by 13% of parents). Parents' expectations of germline genome sequencing, return of results preferences, and recall of results received were assessed. Forty-five parents (of 43 children) were interviewed in depth. At trial enrollment, most parents (63%) believed it was at least "somewhat likely" that their child would receive a clinically relevant germline finding. Almost all expressed a preference to receive a broad range of germline genomic findings, including variants of uncertain significance (88%). Some (29%) inaccurately recalled receiving a clinically relevant germline finding. Qualitatively, parents expressed confusion and uncertainty after the return of their child's genome sequencing results by their child's clinician. Many parents of children with poor-prognosis childhood cancer enrolled in a precision medicine trial expect their child may have an underlying cancer predisposition syndrome. They wish to receive a wide scope of information from germline genome sequencing but may feel confused by the reporting of trial results.

Breast Cancer, a Global Health Crisis

Breast cancer is still a public health problem worldwide and is currently the most common tumor in the world. Breast cancer is a life-threatening disease in women and the leading cause of death in the female population. Breast cancer is a heterogeneous disorder with different molecular subtypes and biological characteristics, with different therapeutic functions and clinical outcomes for each molecular subtype. Furthermore, the treatment of BC is complicated by intratumoral complexity. Consequently, breast cancer risk assessment is an important part of public health. Precision medicine for breast cancer is a practice for diagnosis, treatment, screening and prevention of the disease that takes into account the patient's genetic makeup. Therefore, by identifying women who are at high risk of breast cancer, it is possible to make personalized recommendations regarding screening methods, the age at which breast screening should begin, the frequency of completing screenings, and individual counselling.

Parents' and adolescents' perspectives and understanding of information about childhood cancer precision medicine.

Precision medicine is projected to become integral to childhood cancer care. As such, it is essential to support families to understand what precision medicine entails. A total of 182 parents and 23 adolescent patients participating in Precision Medicine for Children with Cancer (PRISM), an Australian precision medicine clinical trial for high-risk childhood cancer, completed questionnaires after study enrollment (time 0 [T0]). Of the parents, 108 completed a questionnaire and 45 completed an interview following return of precision medicine results (time 1 [T1]). We analyzed the mixed-methods data comprising measures exploring families' perceptions and understanding of PRISM's participant information sheet and consent form (PISCF), and factors associated with understanding. Most parents were satisfied with the PISCF, rating it as at least "somewhat" clearly presented (n=160/175; 91%) and informative (n=158/175; 90%). Many suggested improvements including the use of clearer language and a more visually engaging format. Parents' actual understanding of precision medicine was low on average, but scores improved between T0 and T1 (55.8/100-60.0/100; p=.012). Parents from culturally and/or linguistically diverse backgrounds (n=42/177; 25%) had lower actual understanding scores than those from a Western/European background whose first language was English (p=.010). There was little correlation between parents' perceived and actual understanding scores (p=.794; Pearson correlation -0.020; 95% CI, -0.169 to 0.116). Most adolescent patients read the PISCF either "briefly" or "not at all" (70%) and had a perceived understanding score of 63.6/100 on average. Our study revealed gaps in families' understanding of childhood cancer precision medicine. We highlighted areas for potential intervention such as through targeted information resources. Precision medicine is projected to become part of the standard of care for children with cancer. Precision medicine aims to give the right treatment to the right patient and involves several complex techniques, many of which may be challenging to understand. Our study analyzed questionnaire and interview data from parents and adolescent patients enrolled in an Australian precision medicine trial. Findings revealed gaps in families' understanding of childhood cancer precision medicine. Drawing on parents' suggestions and the literature, we make brief recommendations about improving information provision to families, such as through targeted information resources.

Precision Medicine Is Changing the Roles of Healthcare Professionals, Scientists, and Research Staff: Learnings from a Childhood Cancer Precision Medicine Trial.

Precision medicine programs aim to utilize novel technologies to identify personalized treatments for children with cancer. Delivering these programs requires interdisciplinary efforts, yet the many groups involved are understudied. This study explored the experiences of a broad range of professionals delivering Australia's first precision medicine trial for children with poor-prognosis cancer: the PRecISion Medicine for Children with Cancer (PRISM) national clinical trial of the Zero Childhood Cancer Program. We conducted semi-structured interviews with 85 PRISM professionals from eight professional groups, including oncologists, surgeons, clinical research associates, scientists, genetic professionals, pathologists, animal care technicians, and nurses. We analyzed interviews thematically. Professionals shared that precision medicine can add complexity to their role and result in less certain outcomes for families. Although many participants described experiencing a greater emotional impact from their work, most expressed very positive views about the impact of precision medicine on their profession and its future potential. Most reported navigating precision medicine without formal training. Each group described unique challenges involved in adapting to precision medicine in their profession. Addressing training gaps and meeting the specific needs of many professional groups involved in precision medicine will be essential to ensure the successful implementation of standard care.

Targeted Therapies and Developing Precision Medicine in Gastric Cancer.

Gastric cancer is an aggressive disease with survival remaining poor in the advanced setting. More than a decade after the first targeted treatment was approved, still only HER2, MSI and PDL-1 status have reached everyday practice in terms of guiding treatment options for these patients. However, various new targets and novel treatments have recently been investigated and have shown promise in improving survival outcomes. In this review, we will summarise previous and currently ongoing studies on predictive biomarkers, possible new targeted treatments, potential reasons for conflicting trial results and hope for the future of precision medicine in gastric cancer.

Liver organoids: a promising three-dimensional model for insights and innovations in tumor progression and precision medicine of liver cancer.

Primary liver cancer (PLC) is one type of cancer with high incidence rate and high mortality rate in the worldwide. Systemic therapy is the major treatment for PLC, including surgical resection, immunotherapy and targeted therapy. However, mainly due to the heterogeneity of tumors, responses to the above drug therapy differ from person to person, indicating the urgent needs for personalized treatment for PLC. Organoids are 3D models derived from adult liver tissues or pluripotent stem cells. Based on the ability to recapitulate the genetic and functional features of in vivo tissues, organoids have assisted biomedical research to make tremendous progress in understanding disease origin, progression and treatment strategies since their invention and application. In liver cancer research, liver organoids contribute greatly to reflecting the heterogeneity of liver cancer and restoring tumor microenvironment (TME) by co-organizing tumor vasculature and stromal components in vitro. Therefore, they provide a promising platform for further investigation into the biology of liver cancer, drug screening and precision medicine for PLC. In this review, we discuss the recent advances of liver organoids in liver cancer, in terms of generation methods, application in precision medicine and TME modeling.

IMPRESS-Norway: Improving public cancer care by implementing precision cancer medicine in Norway.

e15188 Background: Precision cancer medicine is evolving rapidly, with new drugs and biomarkers being developed. Advanced molecular diagnostics is a prerequisite for using some of the drugs, which might be approved on small or large subsets of patients. Drugs targeting a specific pathway or gene aberration, might be efficient in other tumour types harbouring the same molecular alteration, but not yet tried in randomized trials due to limited number of patients. This indicates that patients might benefit drugs that are on the market, not available for patients outside the existing indication. Methods: In this national-wide, investigator-initiated, prospective, open-label, non-randomized combined basket- and umbrella-trial, patients are enrolled into multiple parallel treatment cohorts. Patients with progressive disease on standard therapy, are eligible. Each cohort is defined by the patient’s tumour type, molecular profile, and study drug. Treatment outcome in each cohort is assessed by using a Simon two-stage-like ‘admissible’ monitoring plan to identify evidence of clinical activity. All drugs available in IMPRESS-Norway have regulatory approval and are funded by pharmaceutical companies. Currently, 21 drugs are provided by six different pharmaceutical companies, and we are in process to acquire additional drugs for patients in this study. Molecular diagnostics with the TSO-500 gene panel are funded by the public health care system. In addition, patients included are offered analyses of circulating tumour DNA (ctDNA). The primary objective is to evaluate clinical benefit of treatment at 16 weeks of treatment, defined as complete response, partial response, or stable disease. Results: IMPRESS-Norway opened for accrual at April 1st 2021. As of January 24, 2023, tumour cells from 791 patients with advanced cancer, have been analysed with TSO-500, and 662 patients had been discussed at the national molecular tumour board. 150 patients (23%) were allocated to therapy in different treatment-cohorts in IMPRESS-Norway, and 11% were referred to other ongoing clinical studies or early access programs. Extended and updated data and frequency of targetable molecular alteration will be presented. Conclusions: Patients with advanced cancer progressing on standard treatment are referred to treatment in IMPRESS-Norway after advanced molecular diagnostics. Genetic alterations indicating benefit of the drugs currently available in the study, are detected in 23% of 662 evaluated patients. Clinical trial information: NCT04817956 .

Concordance between cryobiopsy and forceps biopsy specimens in assessment of immunohistochemistry staining for non-small cell lung carcinoma.

Cryobiopsy is recently being promoted for biopsy of tumors in the lung periphery in precision medicine for lung cancer; the obtained tissue samples have been reported to be more useful compared to those obtained using forceps, because of the larger volume and higher quality. However, the influence of freezing and thawing of tissues when performing cryobiopsy on the results of immunohistochemistry (IHC) has not been completely understood. In this study, consecutive patients who underwent diagnostic bronchoscopy with cryobiopsy for peripheral pulmonary lesions (PPLs) at our institution between June 2017 and November 2021 were reviewed retrospectively. Specimens of diagnosed cases of unresectable or recurrent non-small cell lung carcinoma (NSCLC) were selected. We compared the results of IHC assessment for programmed death-ligand 1 (PD-L1), human epidermal growth factor receptor 2 (HER2), and human epidermal growth factor receptor 3 (HER3) in cryobiopsy specimens versus conventional forceps biopsy specimens from the same site in the same procedure. Twenty-four of 40 patients were male (60%). The most frequent histologic type of cancer was adenocarcinoma (n=31, 77.5%), followed by NSCLC (n=4, 10%), squamous cell carcinoma (n=3, 7.5%), and others (n=2, 5%). The concordance rates of the tumor proportion scores (TPSs) for PD-L1, IHC score for HER2 and, IHC scores for HER3 were 85%, 72.5%, and 75%, respectively; the weighted kappa were 0.835, 0.637, and 0.697, respectively. Freezing and thawing associated with cryobiopsy had virtually no effect on the results of IHC. We suggest that cryobiopsy specimens would therefore be ideal for precision medicine and translational research.

FLEX, a real-world evidence full transcriptome study of 30,000 patients with early-stage breast cancer.

TPS621 Background: Clinical trials have been an invaluable tool in providing improvements in the discovery, treatment, and quality of life for various diseases and disorders including breast cancer, which impacts millions of people each year. Historically, patient trial populations have not been racially diverse due to several factors such as bias, healthcare distrust, access, and eligibility criteria. However, current efforts are focused on improving diversity and inclusion to promote efficacy and health equity across all races/ethnicities. The ongoing, multi-center FLEX trial (NCT03053193), which pairs clinical data and full transcriptome expression data, seeks to enroll 30,000 patients to accelerate real world research. Due to the size of the database, it is also expected to capture patients typically underrepresented in clinical trials. Methods: FLEX is the first of its kind, prospective, observational trial that enrolls patients who are ≥ 18 years old with histologically proven stage I-III breast cancer with up to 3 positive lymph nodes. Patient eligibility for study enrollment include standard of care MammaPrint testing with or without BluePrint and consent to clinically annotated full transcriptome data collection. The study infrastructure facilitates the generation of hypotheses for targeted sub-studies. The FLEX network fosters collaboration with 114 sites, including one site in Greece and Israel, encouraging participating investigators to initiate sub-studies that can address research questions that are important for breast cancer management. All proposed sub-studies are vetted and approved by Research and Scientific Review Committees. Since launching in April 2017, 12,569 patients have been enrolled including those who have been historically underrepresented in trials (African American n= 1025; Latin n= 341; Asian n=156). Forty-two investigator initiated sub-studies have been approved and are in progress, with 40 abstracts accepted in national and international congresses. Five ongoing sub-studies within FLEX address differences in underlying biology and treatment response/management among African American, Latina, and Asian American patients with early-stage breast cancer. These studies provide a broader understanding of how differential gene expression patterns unique to racial/ethnic groups can impact treatment outcomes. With the large FLEX database, enrollment and sub-studies are extended to other racial/ethnic groups that are underrepresented in clinical trials, but not limited to specific groups. Overall, the FLEX study strives to use full transcriptome data to improve precision medicine in early-stage breast cancer. Clinical trial information: NCT03053193 .

Overcoming barriers to adoption of precision medicine in community oncology centers in the rural southeastern United States using novel informatics tools and academic collaborations.

e13514 Background: Comprehensive genomic profiling (CGP) is an important tool to identify actionable biomarkers and guide cancer therapy. However, patient (pt) race, socioeconomic status, and clinical setting are associated with lower access to CGP, targeted therapies, and clinical trials. To address this, we expanded a novel framework for genomic data management and clinical decision support developed at a large academic medical center to a network of affiliated community cancer centers located in rural, traditionally underserved communities. Methods: The Duke Precision Cancer Medicine Initiative (PCMI) developed a centralized database to aggregate and normalize CGP results. This database enables CGP review by a multi-disciplinary Molecular Tumor Board (MTB). PCMI established a protocol that allows the MTB to review CGP results and relevant clinical data for consented patients. This protocol opened enrollment at four DCN-affiliated cancer centers in rural North Carolina. Clinical recommendations are captured in a standard note and returned to DCN providers following each review. Our protocol also includes an anonymous survey sent to oncology providers asking about barriers to access and utilization of CGP. Results: Between Jan 2022 and Jan 2023, 62 pts were enrolled and had CGP results reviewed by the MTB; 13 pts (21.0%) were Native American and 20 (32.3%) were Black. 61 actionable genomic alterations were identified from 38 pts, including 16 (25.6%) that molecularly matched clinical trial inclusion criteria. Most DCN providers reported being comfortable ordering (14/20) CGP though fewer expressed comfort with interpretation (9/20) CGP; provider-reported barriers included cost/insurance for targeted therapies (12/20) and distance to clinical trials (14/20). Conclusions: Successful academic-community partnerships to expand access to CGP, clinical trials, and targeted therapies are feasible when supported by fit-for-purpose informatics tools and scalable workflows. Additional work is required to develop comprehensive solutions that ensure equal access to CGP and precision medicine for all patients. [Table: see text]

Improving guideline-concordant biomarker testing through implementation of a precision cancer medicine steward.

e18706 Background: Gaps in guideline-concordant cancer biomarker testing exist in real-world clinical practice. Medically underserved populations, in particular, face significant challenges to accessing the latest advances in cancer diagnostics. As community cancer programs work to expand their approach to precision medicine, some have created a precision medicine “steward” who acts as a point person for removing barriers to biomarker testing. The Association of Community Cancer Centers (ACCC) explored the clinical utility, impact, and feasibility of having a precision medicine steward on the multidisciplinary cancer care team. Methods: ACCC held a series of focus groups and interviews with a diverse group of stakeholders to explore how cancer programs had justified, hired, trained, and utilized precision medicine stewards to improve guideline-concordant biomarker testing rates. ACCC examined select job descriptions, learned how stewards helped improve biomarker testing processes, and developed a framework for how a steward can fit into cancer care teams’ clinical and operational workflows. Results: Precision cancer medicine stewards can help improve biomarker test ordering processes. In one member program, turnaround time from test ordering to receipt of results decreased from an average of 24 days to 12 days and the quantity non-sufficient rate of testing decreased by five percent. Stewards also helped to improve the digitization of test orders, streamline prior authorizations, track tissue specimens, and notify oncologists when quantity of tissue was not adequate for testing. Stewards contributed to precision medicine workgroups that vetted reference laboratories, tracked key performance indicators around biomarker testing, and prioritized opportunities to reduce testing disparities. ACCC also collated examples of job titles, job descriptions, and role responsibilities of precision medicine stewards to share across member programs and practices. Conclusions: Guideline-concordant biomarker testing requires multiple complex steps and careful care coordination. Precision cancer medicine stewards have been shown to improve testing-related processes, decrease the time from ordering to receipt of results, and assist with prior authorizations. ACCC will work to further highlight their contributions on the multidisciplinary cancer care team and document more evidence of their return on investment for cancer programs and practices.

Decoding of exosome heterogeneity for cancer theranostics.

Extracellular Vesicles (EVs) discovery establishes a new milestone in cancer research. It explains cancer biology in a new way. EVs classified some significant subclasses such as macrovesicle (originated from plasma membrane), apoptotic bodies (originated from the plasma membrane and endoplasmic reticulum), and exosomes (originated from endosomes).1 The theranostic signature of exosomes in cancer healing is impressive, but its heterogeneity leads most complicated domain of research. Therefore we comment on decoding exosome heterogeneity for future efficiency and effective cancer theranostics development. EVs are the cell-secreted one of the most important entities. The exosome attracted much attention due to its versatile uses. Overall, its participation in intercellular communication and its inner cargos (DNA, RNA, proteins, lipids and glycan)2 can reprogram the recipient cells. In addition, it also shows the healthy or pathologic complication status of the parent cells. In cancer, tumor and exosomes interlink a complex chapter of cancer biology. Exosomes play an important role in accelerated tumor growth, immune cell reprogramming,2 angiogenesis,3 extracellular matrix remodelling,4, 5 metastasis,4, 5 epithelial-mesenchymal transition (EMT),4, 5 organ-specific metastasis,5, 6 drug resistance and cancer stem cell development.3, 4 Clinically aspect, the exosome is the source of the cancer biomarkers.7-9 Exosome heterogeneity1 is evolving into a major conflict in cancer biomarker and therapeutic research.10 The exosome heterogeneity (Figure 1) is based on several facts such as origin, size, quantity, and internal molecular diversity.1 Exosome size distribution is the most complicated side of tumor-derived exosomes (TEXs). Scientific evidence shows that the same cells release differently-sized exosomes. This size-oriented biodiversity is reflected in using different isolation methods.9, 10 The tumor cells release more exosomes compared to healthy cells. The higher release of exosomes from tumor cells depends on several factors, such as drug and therapeutic exposures, hypoxic conditions, and senescence. The functional diversity of exosomes is related to the surface molecular expression and inner cargos of exosomes. All these complicated/complex parameters lead to a challenging ecosystem development of exosome-based cancer theragnostics (combination of biomarkers and therapeutics research). This scenario requires a solution to solve these challenges. Based on several innovative nano platform-based approaches transform these challenges into an opportunity for exosome researcher in a detailed exploration of exosome.11 Exosomes isolation, size and quantity related complication solved via microfluidic device, fluorescence antibody based exosome tracking, Nanoparticle tracking analysis (NTA) (above 60 nm exosome size challenging for its application),12, 13 magnetic and surface plasma resonance principle based single exosome screening,1 advanced sensitive flow cytometry (it is capable of the separation of exosome subpopulation) and electrophoresis chip. Molecular profiling of exosomes is one of the most critical tasks revealing the functional diversity of bioactive cargo molecules of exosomes. Droplet digital polymerase chain reaction (it is sensitive to the detection of rear mutations in tumor-derived exosomes),1 microfluidic technology combined with a chip system, and an electrochemical principle-based micro RNA profiling of exosomes explain the cancer complication of a new dimension.1 The downstream process of exosome profiling needs a muti-omics approach for proper molecular diversity to understand.1 The single cells exosome profiling approach combines with machine learning for more precision cancer marker development.14 All these technological advancements support constructing the next-generation promising cancer theranostic era based on exosomes.15, 16 Finally, decoding exosome heterogeneity opens a new door for exosome-based precision medicine17 and vaccines18 for cancer. We hope this article encourages large-scale EV research to explore a single exosome profiling approach and future exosome-based cancer precision medicine development. Not applicable. The authors declare no conflict of interest. There is no funding for this study.

Precision Medicine in Head and Neck Cancer

Technological advancement in human genome analysis and ICT (information &amp; communication technologies) brought ‘precision medicine’ into our clinical practice. Precision medicine is a novel medical approach that provides personalized treatments tailored to each individual by precisely segmenting patient populations, based on robust data including a person’s genetic information, disease information, lifestyle information, etc. Precision medicine has a potential to be applied to treating a range of tumors, in addition to non-small cell lung cancer, in which precision oncology has been actively practiced. In this article, we are reviewing precision medicine in head and neck cancer (HNC) with focus on tumor agnostic biomarkers and treatments such as &lt;i&gt;NTRK&lt;/i&gt;, MSI-H/dMMR, TMB-H and &lt;i&gt;BRAF&lt;/i&gt; V600E, all of which were recently approved by U.S. Food and Drug Administration (FDA).

Modeling the Tumor Microenvironment and Cancer Immunotherapy in Next-Generation Humanized Mice.

Cancer immunotherapy has brought significant clinical benefits to numerous patients with malignant disease. However, only a fraction of patients experiences complete and durable responses to currently available immunotherapies. This highlights the need for more effective immunotherapies, combination treatments and predictive biomarkers. The molecular properties of a tumor, intratumor heterogeneity and the tumor immune microenvironment decisively shape tumor evolution, metastasis and therapy resistance and are therefore key targets for precision cancer medicine. Humanized mice that support the engraftment of patient-derived tumors and recapitulate the human tumor immune microenvironment of patients represent a promising preclinical model to address fundamental questions in precision immuno-oncology and cancer immunotherapy. In this review, we provide an overview of next-generation humanized mouse models suitable for the establishment and study of patient-derived tumors. Furthermore, we discuss the opportunities and challenges of modeling the tumor immune microenvironment and testing a variety of immunotherapeutic approaches using human immune system mouse models.

Abstract CT019: Phase I/II study of the PARP inhibitor olaparib and ATR inhibitor ceralasertib in children with advanced malignancies: Arm N of the AcSé-ESMART trial

Abstract Background: AcSé-ESMART is a European proof-of-concept, phase I/II, platform precision cancer medicine trial designed to explore targeted agents in a molecularly enriched population. Arm N explores the PARP inhibitor (PARPi) olaparib (ola) in combination with the Ataxia telangiectasia mutated rad3 related (ATR) inhibitor (ATRi) ceralasertib (cer). In pediatric cancer, the rationale for this combination is twofold: i) Many cancers show evidence of a constitutively active ATR pathway due to endogenous replication/transcription stress (RS) which can be targeted by ATRi. PARPi in this setting serves as additional replication stressor/ATRi sensitizer. ii) Classical BRCA alterations are rare and alterations conferring homologous recombination deficiency (HRD) likely require a combination approach including PARPi. This is a first-in-child study and we here report the results of the Phase I dose escalation part. Methods: Children and adolescents with relapsed or refractory cancer and advanced molecular profiling at relapse were eligible. All patients had to have molecular alterations consistent with HRD or RS in their tumor. Ola was administered orally twice daily (BID) continuously and cer orally BID on days 1-14 of a 28-day cycle. Dose level (DL) 1 was ola 150/100/50 mg BID and cer 80/40/30 mg BID in age group 12-18/6-&amp;lt;12/3-&amp;lt;6 years, respectively. Dose-escalation followed a Boin design, 12 patients treated at the recommended Phase II dose (RP2D) were required to conclude the Phase I part. Plasma for pharmacokinetics (PK) of both drugs was collected during Cycle 1. Results: Eighteen patients (8 sarcomas, 5 central nervous system tumors, 4 neuroblastomas, 1 carcinoma) with a median age of 16 years (range, 4;24) were enrolled over 3 dose levels between Feb 2021 and Sep 2022 and received a median of 3.5 cycles (range 1-12+; data cut-off Jan 2023). The combination was well tolerated overall, toxicity was mainly hematologic (thrombocytopenia, neutropenia, anemia) and gastrointestinal (nausea/vomiting). Five patients encountered dose-limiting toxicities (thrombocytopenia grade 3/4 requiring platelet transfusions &amp;gt; 7 days in all, and grade 4 neutropenia for &amp;gt; 7 days or with documented infection in 1 patient each; 0/3 DL-1, 2/12 in DL1 and 3/3 in DL2), suggesting DL1 as RP2D. One confirmed partial response (PR) was observed in a patient with pinealoblastoma (FANCA VUS), a prolonged stable disease converted to a PR after cycle 9 in a neuroblastoma (11q loss, ATRX VUS, in cycle 10). Four patients are ongoing in cycle 5/6/10/12, respectively. PK and retrospective biomarker analysis are ongoing to identify factors associated with clinical benefit and data will be presented. Conclusions: Ola and cer in combination are well tolerated. Recruitment in two expansion cohorts (HRD and RS) is ongoing at the RP2D, including confirmation of RP2D in younger children. Citation Format: Susanne A. Gatz, Alba Rubio San Simón, Baptiste Archambaud, Samuel Abbou, Morgane Cleirec, Amaury Leruste, Anne-Sophie Defachelles, Nicolas André, Jonathan Rubino, Souad Nebchi, Windy Rondof, Simon A. Smith, Peter G. Mortimer, Bienvenu Loembé, Gwenael Le Teuff, Gilles Vassal, Birgit Geoerger. Phase I/II study of the PARP inhibitor olaparib and ATR inhibitor ceralasertib in children with advanced malignancies: Arm N of the AcSé-ESMART trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT019.

A new tumorgraft panel to accelerate precision medicine in prostate cancer.

Despite the significant advances in the management of advanced prostate cancer (PCa), metastatic PCa is currently considered incurable. For further investigations in precision treatment, the development of preclinical models representing the complex prostate tumor heterogeneity are mandatory. Accordingly, we aimed to establish a resource of patient-derived xenograft (PDX) models that exemplify each phase of this multistage disease for accurate and rapid evaluation of candidate therapies. Fresh tumor samples along with normal corresponding tissues were obtained directly from patients at surgery. To ensure that the established models reproduce the main features of patient's tumor, both PDX tumors at multiple passages and patient's primary tumors, were processed for histological characteristics. STR profile analyses were also performed to confirm patient identity. Finally, the responses of the PDX models to androgen deprivation, PARP inhibitors and chemotherapy were also evaluated. In this study, we described the development and characterization of 5 new PDX models of PCa. Within this collection, hormone-naïve, androgen-sensitive and castration-resistant (CRPC) primary tumors as well as prostate carcinoma with neuroendocrine differentiation (CRPC-NE) were represented. Interestingly, the comprehensive genomic characterization of the models identified recurrent cancer driver alterations in androgen signaling, DNA repair and PI3K, among others. Results were supported by expression patterns highlighting new potential targets among gene drivers and the metabolic pathway. In addition, in vivo results showed heterogeneity of response to androgen deprivation and chemotherapy, like the responses of patients to these treatments. Importantly, the neuroendocrine model has been shown to be responsive to PARP inhibitor. We have developed a biobank of 5 PDX models from hormone-naïve, androgen-sensitive to CRPC primary tumors and CRPC-NE. Increased copy-number alterations and accumulation of mutations within cancer driver genes as well as the metabolism shift are consistent with the increased resistance mechanisms to treatment. The pharmacological characterization suggested that the CRPC-NE could benefit from the PARP inhibitor treatment. Given the difficulties in developing such models, this relevant panel of PDX models of PCa will provide the scientific community with an additional resource for the further development of PDAC research.

Applying CRISPR-Cas9 screens to dissect hematological malignancies

Bit by bit, over the last few decades, functional genomic tools have been piecing together the molecular puzzle driving tumorigenesis in human patients. Nevertheless, our understanding of the role of several genes and regulatory elements that drive critical cancer-associated physiological processes from disease development to progression to spread is very limited, which significantly affects our ability of applying these insights in the context of improved disease management. The recent advent of clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9)-based technology and its application in cancer genomics has, however, allowed the generation of a wealth of knowledge that has helped decipher several critical questions associated with translational cancer research. Precisely, the high-throughput capability coupled with a high level of technological plasticity associated with the CRISPR-Cas9 screens have expanded our horizons from a mere struggle to appreciate cancer as a genetic disease to observing the integrated genomic/epigenomic network of numerous malignancies and correlating it with our present knowledge of drugging strategies to develop innovative approaches for next-generation precision cancer medicine. Specifically, within blood cancers, current CRISPR screens have specifically focused on improving our understanding of drug resistance mechanisms, disease biology, the development of novel therapeutic approaches, and identifying the molecular mechanisms of current therapies, with an underlying aim of improving disease outcomes. Here, we review the development of the CRISPR-Cas9 genome-editing strategy, explicitly focusing on the recent advances in the CRISPR-Cas9-based screening approaches, its current capabilities, limitations, and future applications in the context of hematological malignancies.

Research Progress in Immune Checkpoint Inhibitors Combination Therapy Applied to Non-small Cell Lung Cancer after EGFR Mutation-targeted Therapy Resistance

With the development of precision medicine for lung cancer, targeted therapy has greatly improved the survival and prognosis of patients with advanced non-small cell lung cancer (NSCLC), but the occurrence of acquired drug resistance ultimately leads to patients with no targeted drugs available and no standard treatment options for this group of patients afterwards. The emergence of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced NSCLC. However, due to the unique features of NSCLC with epidermal growth factor receptor (EGFR) mutation, such as immunosuppressive tumor microenvironment (TME), single ICIs treatment has limited clinical benefits in NSCLC patients with EGFR mutation, and the combination of ICIs with chemotherapy and/or targeted therapies is the trend. This review further discusses potential subpopulations with EGFR mutations that may benefit from ICIs treatment, and analyzes how decisions can be made in the era of combined immunotherapy to maximize the efficacy of ICIs treatment in EGFR mutation targeted therapy for NSCLC patients with drug resistance, with the aim of achieving individualized treatment.