Trials For Treatment Of Cancer Research Articles

DNA-PK participates in pre-rRNA biogenesis independent of DNA double-strand break repair.

Although DNA-PK inhibitors (DNA-PK-i) have been applied in clinical trials for cancer treatment, the biomarkers and mechanism of action of DNA-PK-i in tumor cell suppression remain unclear. Here, we observed that a low dose of DNA-PK-i and PARP inhibitor (PARP-i) synthetically suppresses BRCA-deficient tumor cells without inducing DNA double-strand breaks (DSBs). Instead, we found that a fraction of DNA-PK localized inside of nucleoli, where we did not observe obvious DSBs. Moreover, the Ku proteins recognize pre-rRNA that facilitates DNA-PKcs autophosphorylation independent of DNA damage. Ribosomal proteins are also phosphorylated by DNA-PK, which regulates pre-rRNA biogenesis. In addition, DNA-PK-i acts together with PARP-i to suppress pre-rRNA biogenesis and tumor cell growth. Collectively, our studies reveal a DNA damage repair-independent role of DNA-PK-i in tumor suppression.

Protocol for the development of a core outcome set and reporting guidelines for locoregional treatment in neoadjuvant systemic breast cancer treatment trials: the PRECEDENT project

IntroductionNeoadjuvant systemic anticancer therapy (neoSACT) is increasingly used in the treatment of early breast cancer. Response to therapy is prognostic and allows locoregional and adjuvant systemic treatments to be tailored...

FAK-LINC01089 negative regulatory loop controls chemoresistance and progression of small cell lung cancer.

The focal adhesion kinase (FAK) tyrosine kinase is activated and upregulated in multiple cancer types including small cell lung cancer (SCLC). However, FAK inhibitors have shown limited efficacy in clinical trials for cancer treatment. With the aim of identifying potential therapeutic strategies to inhibit FAK for cancer treatment, we investigated long non-coding RNAs (lncRNAs) that potentially regulate FAK in SCLC. In this study, we identified a long non-coding RNA LINC01089 that binds and inhibits FAK phosphorylation (activation). Expression analysis revealed that LINC01089 was downregulated in SCLC tissues and negatively correlated with chemoresistance and survival in SCLC patients. Functionally, LINC01089 inhibited chemoresistance and progression of SCLC in vitro and in vivo. Mechanistically, LINC01089 inhibits FAK activation by blocking binding with Src and talin kinases, while FAK negatively regulates LINC01089 transcription by activating the ERK signaling pathway to recruit the REST transcription factor. Furthermore, LINC01089-FAK axis mediates the expression of drug resist-related genes by modulating YBX1 phosphorylation, leading to drug resistance in SCLC. Intriguingly, the FAK-LINC01089 interaction depends on the co-occurrence of the novel FAK variant and the non-conserved region of LINC01089 in primates. In Conclusion, our results indicated that LINC01089 may serve as a novel high-efficiency FAK inhibitor and the FAK-LINC01089 axis represents a valuable prognostic biomarker and potential therapeutic target in SCLC.

National Estimates of the Participation of Patients With Cancer in Clinical Research Studies Based on Commission on Cancer Accreditation Data.

National estimates of cancer clinical trial participation are nearly two decades old and have focused solely on enrollment to treatment trials, which does not reflect the willingness of patients to contribute to other elements of clinical research. We determined inclusive, contemporary estimates of clinical trial participation for adults with cancer using a national sample of data from the Commission on Cancer (CoC). The data were obtained from accreditation information submitted by the 1,200 CoC programs, which represent more than 70% of all cancer cases diagnosed in the United States each year. Deidentified, institution-level aggregate counts of annual enrollment to treatment, biorepository, diagnostic, economic, genetic, prevention, quality-of-life (QOL), and registry studies were examined. Overall, study-type estimates for the period 2013-2017 were estimated. Multiple imputation by chained equations was used to account for missing data, with summary estimates calculated separately by type of program (eg, National Cancer Institute [NCI]-designated cancer centers) and pooled. The overall estimated patient participation rate to cancer treatment trials was 7.1%. Patients with cancer participated in a wide variety of other studies, including biorepository (12.9%), registry (7.3%), genetic (3.6%), QOL (2.8%), diagnostic (2.5%), and economic (2.4%) studies. Treatment trial enrollment was 21.6% at NCI-designated comprehensive cancer centers, 5.4% at academic (non-NCI-designated) comprehensive cancer programs, 5.7% at integrated network cancer programs, and 4.1% at community programs. One in five patients (21.9%) participated in one or more cancer clinical research studies. In a first-time use of national accreditation information from the CoC, enrollment to cancer treatment trials was 7.1%, higher than historical estimates of <5%. Patients participated in a diverse set of other study types. Contributions of adult patients with cancer to clinical research is more common than previously understood.

Geographic disparity in the distribution of cancer clinical trials in the United States and the associated factors.

Little is known regarding the geographic disparity in the distribution of phase 1-3 clinical trials of new cancer treatments in the US and the associated factors. To examine county-level variation in the number of phase 1-3 cancer clinical trials and the associations between county characteristics and having phase 1-3 cancer clinical trials. We identified phase 1-3 cancer clinical trials started in the US between January 2008 and December 2022 from the Aggregate Analysis of ClinicalTrials.gov database. We analyzed the distribution of phase 1-3 cancer clinical trials at the county level. Using a mixed-effects regression with states as random intercepts, we estimated the associations between a county's median age, median household income, percentage of population from racial and ethnic minority groups, proportion of population aged 25 years or older with an educational attainment of bachelor's degree or higher, rurality, cancer incidence rate, and number of medical oncologists per population with having any phase 1-3 cancer clinical trial in a county. After excluding trials that were suspended, terminated, and withdrawn, a total of 14,977 phase 1-3 cancer clinical trials started in the United States between January 2008 and December 2022 were included in the primary analysis. Only 1,333 out of 3,143 counties (42.4%) had 1 or more trial during this period. Counties that were rural, with lower median household income, a less educated population, fewer medical oncologists per population, and lower cancer incidence rates demonstrated a significantly lower likelihood of having phase 1-3 cancer clinical trials. Our study revealed substantial geographic disparities in the distribution of phase 1-3 cancer clinical trials. Limited trial availability in low-income, low-education, low-oncologist, and rural areas can be a significant barrier to patient participation, potentially hindering adoption and worsening outcomes in disadvantaged populations.

Radiotherapy Combined with a Radiosensitizer for Bacillus Calmette-Guérin–unresponsive Non–muscle-invasive Carcinoma In Situ Bladder Cancer: An Open-label, Single-arm, Multicenter, Phase 2 European Organisation for Research and Treatment of Cancer Trial

Radical cystectomy with pelvic lymph node dissection and urinary diversion is the standard of care for patients with bacillus Calmette-Guérin (BCG)-unresponsive non–muscle-invasive bladder cancer (NMIBC). However, many patients are unwilling or unable to undergo such major surgery associated with high morbidity and a negative impact on quality of life. Chemoradiotherapy is an established treatment option for muscle-invasive bladder cancer. However, it has not been investigated adequately in NMIBC until now. The European Organisation for Research and Treatment of Cancer (EORTC) 2235 study (NCT06310369) is designed as a multicenter, prospective, international, phase 2 trial of moderate hypofractionated radiotherapy combined with a radiosensitizer in BCG-unresponsive NMIBC patients with carcinoma in situ (CIS) who are not eligible for or declined to undergo radical cystectomy. Patients who have received nadofaragene firadenovec or TAR-200 are eligible. The primary endpoint is the 6-mo complete response (CR) rate defined by the absence of CIS proven by a control biopsy of the bladder. The secondary endpoints include overall survival, progression-free survival, durability of CR, grade 3–4 adverse events rate, patients’ quality of life, and organ preservation rate. Patient summaryIntravesical instillation of bacillus Calmette-Guérin is the standard treatment of non–muscle-invasive, also coined as superficial, bladder cancer. In case the cancer recurs, even superficially, there is no other proven treatment than a radical cystectomy—the surgical removal of the bladder. Although the surgical technique has improved dramatically over the past few years, it remains contraindicated in patients with severe comorbidities. In addition, because it affects the quality of life, patients may reject this option. This study will assess the efficacy of external beam radiotherapy, a robust alternative to surgery in muscle-invasive bladder cancer. Radiotherapy will be administered 5 d a week for 4 wk. It will be associated with a “radiosensitizer,” an intravenous or oral drug, during the radiotherapy treatment. The study will measure the proportion of patients remaining recurrence free at 6 mo and thereafter. It will also evaluate the safety of the treatment and its impact on quality of life.

Epigenetic regulation in cancer therapy: From mechanisms to clinical advances

AbstractEpigenetic regulation refers to the alteration of gene expression independent of changes in DNA sequence. It involves chemical modifications such as DNA methylation, histone methylation, and histone acetylation, which are regulated by a coordinated interplay of various regulators to ensure precise spatial and temporal regulation of gene expression. Epigenetic aberrations are commonly observed in cancer and are considered as hallmarks of cancer. In recent years, small molecules targeting specific epigenetic regulators have been developed and are demonstrating promising therapeutic potential in preclinical and clinical trials for cancer treatment. In this review, we summarize the essential regulatory mechanisms and dysfunctions of epigenetic regulators involved in DNA methylation, histone methylation, and histone acetylation during tumor development and progression. Moreover, we discuss the current advances and challenges in cancer epigenetic therapy that target these mechanisms in both hematologic malignancies and solid tumors. Finally, we discuss the potential of combining epigenetic drugs with other therapies, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy, as a promising approach for cancer treatment. Overall, we aim to enhance the understanding of epigenetic regulation in cancer therapy and explore targeted therapeutic strategies based on these mechanisms, to ultimately advance cancer therapy and improve patient prognosis.

A Long Way to Go: A Scenario for Clinical Trials of PI3K Inhibitors in Treating Cancer.

Alterations in PI3K function are directly related to cancer, making PI3K inhibitors suitable options for anticancer therapies. Information on therapy using different types of PI3K inhibitors is available in literature, providing indications of trends in developing new therapies. Although some studies on PI3K inhibitors for cancer treatment provide clinical evidence, they do not allow a careful search for potential PI3K inhibitors conducted by development indicators. Here, we performed a foresight study of clinical trials involving PI3K inhibitors from the past 11years using indicators of clinical evolution to identify technological trends and provide data for supporting recommendations for new study designs. A comprehensive foresight study was designed based on documents from clinical trials on PI3K inhibitors to perform a systematic and comparative analysis, in order to identify technological trends on new cancer therapies. Our results demonstrate that total number of clinical trials has decreased over the years and, currently, there is a clear prevalence of studies using isoform-specific inhibitors in combined interventions. Clinical trials in Phases I and II were the most frequently found in the database, whereas Phase III trials correspond to 7% of studies. The measurement of clinical trials progression using indicators (drugs in Phase III profile, top-10 drugs, and top-10 combined drugs) demonstrated that the 3 new medicines BKM120, IBI-376, and PF-05212384 have a high potential to provide more efficient cancer treatment in combined interventions. These data also include the groups of targets for each drug, providing a useful and reliable source for design new combinations to overcome the resistance and the poor tolerability observed in some PI3K therapies. The establishment of development indicators based on clinical trials for cancer treatment was useful to highlight the clinical investment in 3 new PI3K drugs and the advantages of combine therapy using FDA-approved drugs.

Drug Repositioning and Response Detection Based on Randomized Control Trials for Cancer Treatment - A Review

Drug repositioning is vital in cancer treatment, offering a swift alternative to identify existing drugs repurposable for cancer treatment, bypassing the lengthy and costly traditional drug development process. This approach not only saves resources for the pharmaceutical sector and healthcare systems but also accelerates the discovery of new drugs. Overcoming challenges like data integration and patient classification is crucial in drug repositioning, where methodological advancements utilizing randomized control trials (RCTs) become essential. RCTs provide a systematic way to assess medication efficacy in diverse cancer subpopulations, enhancing the credibility of drug repositioning outcomes. The current study integrates RCTs with advanced data analytics and machine learning to establish a Bayesian Network response detection based on randomized control (BNRD-RC). This approach allows researchers to identify promising drug candidates, predict patient responses, and optimize treatment plans by analyzing diverse datasets, including genomes, proteomics, and clinical records. Beyond personalized treatment, drug repositioning explores medication synergy and combination therapy for rare cancer types. Simulation analysis significantly aids in validating the efficacy and safety of repositioned drugs. Through simulations of clinical scenarios and treatment outcomes, researchers can assess the impact of drug repositioning on patient survival, quality of life, and healthcare costs.

Quality of Surgical Outcome Reporting in Randomised Clinical Trials of Multimodal Rectal Cancer Treatment: A Systematic Review.

Randomised controlled trials (RCTs) continue to provide the best evidence for treatment options, but the quality of reporting in RCTs and the completeness rate of reporting of surgical outcomes and complication data vary widely. The aim of this study was to measure the quality of reporting of the surgical outcome and complication data in RCTs of rectal cancer treatment and whether this quality has changed over time. Eligible articles with the keywords ("rectal cancer" OR "rectal carcinoma") AND ("radiation" OR "radiotherapy") that were RCTs and published in the English, German, Polish, or Italian language were identified by reviewing all abstracts published from 1982 through 2022. Two authors independently screened and analysed all studies. The quality of the surgical outcome and complication data was assessed based on fourteen criteria, and the quality of RCTs was evaluated based on a modified Jadad scale. The primary outcome was the quality of reporting in RCTs and the completeness rate of reporting of surgical results and complication data. A total of 340 articles reporting multimodal therapy outcomes for 143,576 rectal cancer patients were analysed. A total of 7 articles (2%) met all 14 reporting criteria, 13 met 13 criteria, 27 met from 11 to 12 criteria, 36 met from 9 to 10 criteria, 76 met from 7 to 8 criteria, and most articles met fewer than 7 criteria (mean 5.5 criteria). Commonly underreported criteria included complication severity (15% of articles), macroscopic integrity of mesorectal excision (17% of articles), length of stay (18% of articles), number of lymph nodes (21% of articles), distance between the tumour and circumferential resection margin (CRM) (26% of articles), surgical radicality according to the site of the primary tumour (R0 vs. R1 + R2) (29% of articles), and CRM status (38% of articles). Inconsistent surgical outcome and complication data reporting in multimodal rectal cancer treatment RCTs is standard. Standardised reporting of clinical and oncological outcomes should be established to facilitate comparing studies and results of related research topics.

Synthesis and biological evaluation of novel bi-gold mitocans in lung cancer cells.

Mitochondria are promising drug target for cancer treatment. We previously demonstrated that a bi-gold compound BGC2a was more potent than the mono-gold drug auranofin in suppressing cancer cells due to increased gold atom number that led to higher drug accumulation in and thereby inhibition of mitochondria. To exploit the potential of this new strategy, we further designed and synthesized a series of bi-gold mitocans, the compounds targeting mitochondria. The results showed that most of the newly synthesized mitocans exhibited obviously lower IC50 than auranofin, an old drug that is repurposed in clinical trials for cancer treatment. The best mitocan C3P4 was nearly 2-fold more potent than BGC2a in human non-small cell lung cancer A549 cells and mantle cell lymphoma Jeko-1 cells, exhibiting substantial colony formation-suppressing and tumor-suppressing effects in A549 cells xenograft model. C3P4 induced apoptosis in a dose-dependent manner and arrested cell cycle at G0/G1 phase. The mechanistic study showed that C3P4 significantly increased the global reactive oxygen species and mitochondrial superoxide level, and reduced the mitochondrial membrane potential. C3P4 preferentially accumulated in mitochondria as measured by the gold content and substantially inhibited oxygen consumption rate and ATP production. These results further validated our hypothesis that targeting mitochondria would be promising to develop more potent anticancer agents. C3P4 may be further evaluated as a drug candidate for lung cancer treatment.

Abstract A064: My Choices: A multilevel, multicomponent intervention to improve informed decision-making about clinical trial participation among cancer patients

Abstract Background: Knowledge gained through cancer clinical trials (CTs) has been proven critical to preventing, diagnosing and treating the disease, and providing the evidence base for clinical practice. Major advances in cancer treatment, which are essential for improving patients’ outcomes, come from investigations of new therapeutic agents in CTs. Despite the large number of available studies and improvements in public awareness about CTs, participation of underrepresented minorities in clinical research has been persistently low, with only 2-5% of Latinos and African Americans participating in cancer treatment trials. Barriers to participation are multilevel, complex, and multifactorial, including study design, healthcare system barriers, and patient- and medical team-related factors. Structural inequities, social determinants of health (SDoH), distrust of government, patient-doctor communications, cultural and language barriers, and lower levels of health literacy are barriers for Latino and African American populations. Purpose: To improve informed decision-making about cancer CT participation among cancer patients and community members through a bilingual multilevel, multi-communication approach, including: 1) a 2-group parallel randomized controlled educational trial, and 2) a community awareness campaign. Methods: The randomized study involves 400 patients from the Mays Cancer Center. The intervention group receives 1) a bilingual educational video on CTs with patients’ testimonials, 2) a low literacy booklet, 3) support from a patient navigator (PN), and 4) Salud America! weekly emails with links to online/social media posts on CT. The control group receives a general fact sheet on CTs. Healthcare providers involved in clinical research are invited to participate in Webinars to raise awareness of implicit bias and the importance of inclusive research. The community intervention features a prospective single-group pre/post design, where participants (400) act as their own controls. They receive an educational session on CTs provided by a community health educator + a low literacy booklet. Results: Focus groups guided the development of the video script, booklet, and educational materials. The short video features real cancer patients sharing their experiences with CTs and how they overcame common barriers. Study recruitment began in February 2023. So far, we have recruited 36 cancer patients with a mean age of 51 years, 80% White and 61% Hispanic/Latino, 64% married, 44% had Medicare/Medicaid; 36% &amp;lt; high school education; and 33% earned &amp;lt;$40K. Preliminary results will be presented. Conclusions: Multilevel interventions involving culturally tailored decision aids (i.e., video, booklet) in combination with PN support can effectively address common barriers influencing patient decision-making, raise awareness of CTs, and increase positive attitudes, intentions, and participation in CTs among groups experiencing SDoH. Citation Format: Patricia Chalela, Vivian Cortez, Armida Flores, Sandra Sivak, Edgar Munoz, Cliff Despres, Callie Rainosek, Alyssa Gonzalez, Mio Kitano, Virginia Kaklamani, Kate Lathrop, Sukeshi Arora, Andrew Brenner, Deepak K. Pruthi, Amelie G. Ramirez. My Choices: A multilevel, multicomponent intervention to improve informed decision-making about clinical trial participation among cancer patients [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A064.

Abstract IA030: Ensuring diversity in clinical trials

Abstract It is well known that minorities, particularly Blacks, are underrepresented in cancer prevention, early detection, and treatment trials. However the mortality rates for Blacks are significantly higher than other race/ethnic groups.  Research suggests that community involvement is integral to solving public health problems, including involvement in clinical trials-a gold standard. Significant racial/ethnic disparities exist in the accrual of participants for clinical trials. Location and cultural aspects of clinical trials influence recruitment and accrual to clinical trials. Being able to identify and resolve social determinants of health is essential for clinical trial participation.   It is increasingly necessary to be aware of defining characteristics, such as location and culture of the populations from which research participants are enrolled. Utilizing embedded community academic sites to adapt clinical trial research in order to increase minority participation in nontherapeutic cancer clinical trials is warranted.  Considerable attention has focused on the need to increase underserved racial and ethnic populations in clinical research, especially in light of the cancer health disparities that disproportionately plague these groups.   Clinical trial design and implementation are time-consuming and require a multistep process that is complicated by other factors, including eligibility criteria for clinical trials for underserved racial and ethnic populations, recruitment processes, and patients’ misconceptions or lack of information about clinical trials. Georgetown-Lombardi National Capital Area Minority/Underserved NCORP (NCI Community Oncology Research Program) coupled with the Ralph Lauren Center for Cancer Prevention will reveal strategies and approaches instrumental to our success.  These efforts resulted in the development of a strong community capacity–building and clinical research cancer recruitment strategy, and  improved engagement of the community in clinical research, thus ensuring diversity in clinical trials.   Citation Format: Lucile Adams-Campbell. Ensuring diversity in clinical trials [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr IA030.

Multi-Level Factors Underlying Racial/Ethnic Inequities in Clinical Trial Participation Among Patients with Hematologic Cancers: Lessons for the Development of Diversity Plans

Background: The US Food &amp; Drug Administration announced that drug sponsors will be required to implement plans to improve racial/ethnic diversity in clinical trials starting in 2024. While historically marginalized racial/ethnic populations are less likely to participate in cancer trials, there is limited information regarding inequities in access to hematologic cancer trials. It is also unknown whether social determinants of health (SDOH) explain racial/ethnic inequities in trial participation. Here we examined the extent to which commonly used trial inclusion criteria and SDOH factors explain racial/ethnic inequities in clinical trial participation among patients with six hematologic cancers. Methods: This retrospective study used the nationwide Flatiron Health electronic health record-derived de-identified database (2011-2022) of adult patients with multiple myeloma, non-Hodgkin's lymphoma (diffuse large B-cell, follicular, or mantle cell lymphoma) or leukemia (chronic lymphocytic or acute myeloid leukemia). Area-level SDOH ( e.g. predominant race/ethnicity - a measure of segregation) characterizing where patients lived were assessed using the American Community Survey census tract data. Patients were followed from initial diagnosis to clinical study drug receipt (a proxy for trial participation), death, or last recorded activity. Associations of race/ethnicity and SDOH factors with trial participation were assessed using cause-specific hazards models adjusted for clinical confounders (diagnosis year, age, sex, and cancer type). To determine which commonly used trial inclusion criteria ( i.e. abnormal creatinine serum [≥ 2] and performance status) and SDOH factors underlie racial/ethnic inequities, mediation analysis was performed using nonlinear multiple additive regression tree models. Results: This study included 51,382 patients (median age: 67 years, 42.2% women; 57.7% non-Latinx [NL] White, 6.9% NL Black, 6.1% Latinx, 29.4% other/unknown). Black and Latinx patients were more likely to live in marginalized areas ( e.g. segregated neighborhoods color and higher percentages of limited English proficiency and low vehicle ownership) than White patients. Overall, 5.6% of patients participated in trials. Patients who received care from community practices or lived in marginalized neighborhoods were less likely to participate in trials. Black (4.2%; hazard ratio [HR] 0.62, 95% confidence interval [CI]: 0.52- 0.73) and Latinx patients (3.7%; HR 0.53, CI: 0.44-0.65) were less likely to participate in trials than White patients (6.4%). Black-White trial inequities were mediated (77%, CI: 42%-117%) by practice type ( e.g., community vs. academic center, 19%, CI: 9%-28%) and area-level SDOH such as segregation (49%, CI: 21%-77%) and vehicle ownership (12%, CI: 1%-24%). Mediators explained 55% (CI: 23%-87%) of the Latinx-White trial participation inequity; area-level SDOH-including segregation (30%, CI: 3%-58%), limited English proficiency (21%, CI: -3% to 45%), and vehicle ownership (17%, CI: 0%-45%)-were the most important mediators. Clinical factors did not substantially mediate racial/ethnic inequities (&amp;lt; 3% proportion mediated). Conclusion: Black and Latinx patients diagnosed with hematologic cancers are 40% to 50% less likely to participate in clinical trials than their White counterparts. SDOH factors explained most of these inequities. These findings suggest that efforts to increase racial/ethnic diversity in cancer trials must address the persistent effects of segregation, along with everyday obstacles to clinical care, such as transportation and language barriers. Without concerted efforts to increase trial participation among historically marginalized racial/ethnic groups, trials may perpetuate inequities in investigational drug access and adversely impact the generalizability of pivotal cancer treatment trials.

Overcoming Immune Checkpoint Therapy Resistance with SHP2 Inhibition in Cancer and Immune Cells: A Review of the Literature and Novel Combinatorial Approaches.

SHP2 (Src Homology 2 Domain-Containing Phosphatase 2) is a protein tyrosine phosphatase widely expressed in various cell types. SHP2 plays a crucial role in different cellular processes, such as cell proliferation, differentiation, and survival. Aberrant activation of SHP2 has been implicated in multiple human cancers and is considered a promising therapeutic target for treating these malignancies. The PTPN11 gene and functions encode SHP2 as a critical signal transduction regulator that interacts with key signaling molecules in both the RAS/ERK and PD-1/PD-L1 pathways; SHP2 is also implicated in T-cell signaling. SHP2 may be inhibited by molecules that cause allosteric (bind to sites other than the active site and attenuate activation) or orthosteric (bind to the active site and stop activation) inhibition or via potent SHP2 degraders. These inhibitors have anti-proliferative effects in cancer cells and suppress tumor growth in preclinical models. In addition, several SHP2 inhibitors are currently in clinical trials for cancer treatment. This review aims to provide an overview of the current research on SHP2 inhibitors, including their mechanism of action, structure-activity relationships, and clinical development, focusing on immune modulation effects and novel therapeutic strategies in the immune-oncology field.

Facilitators and barriers to clinical trial participation among Black women with breast cancer and perspectives on digital solutions to improve clinical trial engagement.

107 Background: Clinical trials are essential for developing novel cancer treatments and improving survival. However, Black women with breast cancer have higher cancer mortality rates compared to non-Black women and are less likely to be enrolled in clinical trials. This study aimed to understand barriers and facilitators to clinical trial participation among Black women with breast cancer to inform the design of a mobile health application (app). Methods: Semi-structured interviews lasting 45-60 minutes were conducted between May and September 2022 with a purposive sample of 20 Black women with breast cancer receiving care in academic and community practices in North Carolina. Participants were asked open-ended questions about their perspective on clinical trial participation. Interviews were digitally recorded, transcribed, and analyzed following a consensus coding-based thematic analysis. Results: Participants represented various age groups ranging from 33 to 76 years, breast cancer hormone receptor/HER 2 status, and stage. Several themes related to facilitators and barriers to clinical trial participation emerged from the interviews. Facilitators included prior experience with participating in clinical trials (cancer treatment, behavioral, and symptom management trials); desire to increase representation of Black women in cancer research to better understand how treatments may affect them differently; benefitting others; and potential for less intensive treatment regimens. Barriers included concern with adverse health effects; fear of new drugs and uncertain therapeutic effect; historical exploitation of Black people participating in research and medical care; lack of representation of Black people participating in clinical research; lack of clinical trial opportunities; concern with the term “trial” and being treated as a guinea pig; and concern with getting a placebo. Most participants were willing to use a mobile health app to obtain trusted information about clinical trials. Recommended content for the app included clinical trial risks and benefits, personal testimonials, link to available clinical trials, and resources to address logistical barriers such as transportation. Most participants also reported the importance of having Black people represented in their healthcare team and health messaging to improve trust in clinical trials. Conclusions: Several barriers and facilitators to clinical trial participation were identified. These findings will inform the content of a mobile health app designed to improve engagement of Black women with breast cancer in clinical trial discussions. Presence of racially representative clinicians and research staff was also noted to improve participation of Black women with breast cancer in clinical trials.

Critical role of heme oxygenase-1 in chaetoglobosin A by triggering reactive oxygen species mediated mitochondrial apoptosis in colorectal cancer

The incidence rate of colorectal cancer (CRC) has been increasing and poses severe threats to human health worldwide and developing effective treatment strategies remains an urgent task. In this study, Chaetoglobosin A (ChA), an endophytic fungal metabolite from the medicinal herb-derived fungus Chaetomium globosum Km1126, was identified as a potent and selective antitumor agent in human CRC. ChA induced growth inhibition of CRC cells in a concentration-dependent manner but did not impair the viability of normal colon cells. ChA triggered mitochondrial intrinsic and caspase-dependent apoptotic cell death. In addition, apoptosis antibody array analysis revealed that expression of Heme oxygenase-1 (HO-1) was significantly increased by ChA. Inhibition of HO-1 increased the sensitivity of CRC cells to ChA, suggesting HO-1 may play a protective role in ChA-mediated cell death. ChA induced cell apoptosis via the induction of reactive oxygen species (ROS) and ROS scavenger (NAC) prevented ChA-induced cell death, mitochondrial dysfunction, and HO-1 activation. ChA promoted the activation of c-Jun N-terminal kinase (JNK), and co-administration of JNK inhibitor or siRNA markedly reversed ChA-mediated apoptosis. ChA significantly decreased the tumor growth without eliciting any organ toxicity or affecting the body weight of the CRC xenograft mice. This is the first study to demonstrate that ChA exhibits promising anti-cancer properties against human CRC both in vitro and in vivo. ChA is a potential therapeutic agent worthy of further development in clinical trials for cancer treatment.

Inhibition of MNK pathway sensitizes nasopharyngeal carcinoma to radiotherapy.

Improving the clinical management of nasopharyngeal carcinoma (NPC) is an unmet need owing to the high incidence of treatment failure caused by radioresistance. In our study, we observed increased phosphorylation of translation initiation factor 4E (eIF4E), regulated by MAP kinase-interacting kinase (MNK), in NPC cells following irradiation treatment. Using siRNA to deplete MNK, we found that radiation-induced eIF4E phosphorylation was eliminated, NPC cell sensitivity to radiation was enhanced, and radioresistant NPC cell viability was reduced. Furthermore, we tested three pharmacological MNK inhibitors (eFT508, CGP57380, and cercosporamide) and found that they were effective against radioresistant NPC cells and synergized with irradiation. In-vivo experiments confirmed that eFT508, at a tolerable dose, inhibited the growth of radioresistant NPC and synergized with radiation in a radiosensitive NPC xenograft model. Our research highlights the activation of MNK-mediated survival mechanisms in NPC in response to radiotherapy and the potential of combining radiation with MNK inhibitors as a sensitizing strategy. Notably, eFT508 is currently being investigated in clinical trials for cancer treatment, and our findings may prompt the initiation of clinical trials using eFT508 in radioresistant NPC patients.

Researcher Experience and Comfort With Telemedicine and Remote Patient Monitoring in Cancer Treatment Trials.

Since the onset of COVID-19, oncology practices across the US have integrated telemedicine (TM) and remote patient monitoring (RPM) into routine care and clinical trials. The extent of provider experience and comfort with TM/RPM in treatment trials, however, is unknown. We surveyed oncology researchers to assess experience and comfort with TM/RPM. Between April 10 and June 1, 2022, we distributed email surveys to US-based members of the American Society of Clinical Oncology (ASCO) whose member records indicated interest or specialization in clinical research. We collected respondent demographic data, clinical trial experience, workplace characteristics, and comfort and experience with TM/RPM use across trial components in phase I and phase II/III trials. TM/RPM was defined as clinical trial-related healthcare and monitoring for patients geographically separated from trial site. There were 141 surveys analyzed (5.1% response rate). Ninety percent of respondents had been Principal Investigators, 98% practiced in a norural site. Most respondents had enrolled patients in phase I (82%) and phase II/III trials (99%). Across all phases and trial components, there was a higher frequency of researcher comfort compared to experience. Regarding remote care in treatment trials, 75% reported using TM, RPM, or both. Among these individuals, 62% had never provided remote care to trial patients before the pandemic. COVID-19 spurred the rise of TM/RPM in cancer treatment trials, and some TM/RPM use continues in this context. Among oncology researchers, higher levels of comfort compared with real-world experience with TM/RPM reveal opportunities for expanding TM/RPM policies and guidelines in oncology research.

Mitigative and anti-inflammatory effects of Trichostatin A against radiation-induced gastrointestinal toxicity and gut microbiota alteration in mice

Purpose Radiation-induced gastrointestinal injury (RIGI) is a serious side effect of abdominal and pelvic radiotherapy, which often limits the treatment of gastrointestinal and gynaecological cancers. RIGI is also observed during accidental radiological or nuclear scenarios with no approved agents available till date to prevent or mitigate RIGI in humans. Trichostatin A (TSA), an epigenetic modulator, has been currently in clinical trials for cancer treatment and is also well known for its antibiotic and antifungal properties. Methods In this study, partial body (abdominal) irradiation mice model was used to investigate the mitigative effect of TSA against gastrointestinal toxicity caused by gamma radiation. Mice were checked for alterations in mean body weight, diarrheal incidence, disease activity index and survival against 15 Gy radiation. Structural abnormalities in intestine and changes in microbiota composition were studied by histopathology and 16S rRNA sequencing of fecal samples respectively. Immunoblotting and biochemical assays were performed to check protein nitrosylation, expression of inflammatory mediators, infiltration of inflammatory cells and changes in pro-inflammatory cytokine. Results TSA administration to C57Bl/6 mice improved radiation induced mean body weight loss, maintained better health score, reduced disease activity index and promoted survival. The 16S rRNA sequencing of fecal DNA demonstrated that TSA influenced the fecal microbiota dynamics with significant alterations in the Firmicutes/Bacteriodetes ratio. TSA effectively mitigated intestinal injury, down-regulated NF-κB, Cox-2, iNOS expression, inhibited PGE2 and protein nitrosylation levels in irradiated intestine. The upregulation of NLRP3-inflammasome complex and infiltrations of inflammatory cells in the inflamed intestine were also prevented by TSA. Subsequently, the myeloperoxidase activity in intestine alongwith serum IL-18 levels was found reduced. Conclusion These findings provide evidence that TSA inhibits inflammatory mediators, alleviates gut dysbiosis, and promotes structural restoration of the irradiated intestine. TSA, therefore, can be considered as a potential agent for mitigation of RIGI in humans.