Oncogenic STAT Transcription Factors as Targets for Cancer Therapy: Innovative Strategies and Clinical Translation.

Despite advances in our understanding of molecular aspects of oncogenesis, cancer remains a leading cause of death. The malignant behavior of a cancer cell is driven by the inappropriate activation of transcription factors. In particular, signal transducers and activators of transcription (STATs), which regulate many critical cellular processes such as proliferation, apoptosis, and differentiation, are frequently activated inappropriately in a wide spectrum of human cancers. Multiple signaling pathways converge on the STATs, highlighting their importance in the development and progression of oncogenic diseases. STAT3 and STAT5 are two members of the STAT protein family that are the most frequently activated in cancers and can drive cancer pathogenesis directly. The development of inhibitors targeting STAT3 and STAT5 has been the subject of intense investigations in the last decade, although effective treatment options remain limited. In this review, we investigate the specific roles of STAT3 and STAT5 in normal physiology and cancer biology, discuss the opportunities and challenges in pharmacologically targeting STAT proteins and their upstream activators, and offer insights into novel therapeutic strategies to identify STAT inhibitors as cancer therapeutics.

The complementary roles of STAT3 and STAT1 in cancer biology: insights into tumor pathogenesis and therapeutic strategies.

STATs are a family of transcription factors that regulate many critical cellular processes such as proliferation, apoptosis, and differentiation. Dysregulation of STATs is frequently observed in tumors and can directly drive cancer pathogenesis. STAT1 and STAT3 are generally viewed as mediating opposite roles in cancer development, with STAT1 suppressing tumorigenesis and STAT3 promoting oncogenesis. In this review, we investigate the specific roles of STAT1 and STAT3 in normal physiology and cancer biology, explore their interactions with each other, and offer insights into therapeutic strategies through modulating their transcriptional activity.

Cycloguanil and Analogues Potently Target DHFR in Cancer Cells to Elicit Anti-Cancer Activity.

Dihydrofolate reductase (DHFR) is an established anti-cancer drug target whose inhibition disrupts folate metabolism and STAT3-dependent gene expression. Cycloguanil was proposed as a DHFR inhibitor in the 1950s and is the active metabolite of clinically approved plasmodium DHFR inhibitor Proguanil. The Cycloguanil scaffold was explored to generate potential cancer therapies in the 1970s. Herein, current computational and chemical biology techniques were employed to re-investigate the anti-cancer activity of Cycloguanil and related compounds. In silico modeling was employed to identify promising Cycloguanil analogues from NCI databases, which were cross-referenced with NCI-60 Human Tumor Cell Line Screening data. Using target engagement assays, it was found that these compounds engage DHFR in cells at sub-nanomolar concentrations; however, growth impairments were not observed until higher concentrations. Folinic acid treatment rescues the viability impairments induced by some, but not all, Cycloguanil analogues, suggesting these compounds may have additional targets. Cycloguanil and its most promising analogue, NSC127159, induced similar metabolite profiles compared to established DHFR inhibitors Methotrexate and Pyrimethamine while also blocking downstream signaling, including STAT3 transcriptional activity. These data confirm that Cycloguanil and its analogues are potent inhibitors of human DHFR, and their anti-cancer activity may be worth further investigation.

To share or not to share: communication of caregiver-reported outcomes when a patient has colorectal cancer.

BACKGROUND: The importance of patient-centered measurement in cancer care has led to recognition of the potential for caregiver-reported outcomes to improve caregiver, patient and healthcare system outcomes. Yet, there is limited evidence to inform caregiver-reported outcome implementation. Our purpose was to generate evidence to inform the meaningful and constructive integration of caregiver-reported outcomes into cancer care to benefit caregivers, including exploration of the question of the extent to which these assessments should be shared with patients. We focused on caregivers of patients with colorectal cancer (CRC) because CRC is common, and associated caregiving can be complex. RESULTS: From our Interpretive Description analysis of qualitative interview data from 78 participants (25 caregivers, 37 patients, and 16 healthcare providers [HCPs]), we identified contrasting perspectives about the sharing of caregiver-reported outcome assessments with patients with CRC. Those who preferred open communication with both the patient and caregiver present considered this essential for supporting the caregiver. The participants who preferred private communication without the patient, cited concern about caregiver- and patient-burden and guilt. Recognizing these perspectives, HCPs described strategies used to navigate sensitivities inherent in preferences for open versus private communication. CONCLUSIONS: The integration of caregiver-reported outcomes into cancer care will require careful consideration of caregiver and patient preferences regarding the communication of caregiver assessments to prevent additional burden.

At the Heart of It All: Emotions of Consequence for the Conceptualization of Caregiver-Reported Outcomes in the Context of Colorectal Cancer.

Colorectal cancer (CRC) can be demanding for primary caregivers; yet, there is insufficient evidence describing the caregiver-reported outcomes (CROs) that matter most to caregivers. CROs refer to caregivers' assessments of their own health status as a result of supporting a patient. The study purpose was to describe the emotions that were most impactful to caregivers of patients with CRC, and how the importance caregivers attribute to these emotions changed from diagnosis throughout treatment. Guided by qualitative Interpretive Description, we analyzed 25 caregiver and 37 CRC patient interviews, either as individuals or as caregiver-patient dyads (six interviews), using inductive coding and constant comparative techniques. We found that the emotional aspect of caring for a patient with CRC was at the heart of caregiving. Caregiver experiences that engendered emotions of consequence included: (1) facing the patient's life-changing diagnosis and an uncertain future, (2) needing to be with the patient throughout the never-ending nightmare of treatment, (3) bearing witness to patient suffering, (4) being worn down by unrelenting caregiver responsibilities, (5) navigating their relationship, and (6) enduring unwanted change. The broad range of emotions important to caregivers contributes to comprehensive foundational evidence for future conceptualization and the use of CROs.

Distinct Features of Psychosocial Distress of Adolescents and Young Adults with Cancer Compared to Adults at Diagnosis: Patient-Reported Domains of Concern.

Purpose: Adolescents and young adults (AYA) (18-40) are a population of patients with cancer, who have distinctive developmental and psychosocial pressures. Using validated distress screening tools, we investigated psychosocial needs of AYA compared to older adults with cancer at diagnosis. Methods: AYA and older adult patients from British Columbia, Canada, between 2011 and 2016, who completed the Canadian Problem Checklist (CPC) and the PsychoSocial Screen for Cancer-Revised (PSSCAN-R) within 6 months of their cancer diagnosis were included in the study. Emotional, informational, physical, practical, social, and spiritual domain concerns are identified using the CPC. Psychosocial needs and distress are evaluated using the PSSCAN-R. Baseline demographics were obtained from the cancer registry. Based on gender, primary tumor site, and presence of metastasis, a 3:1 case match was performed with older adults (>40 years old). Statistical analyses included Chi square and Fisher's exact tests. Results: Two thousand and forty five AYA were case matched with 6050 older adults. Majority of patients were female (61.9%), and at diagnosis, 12.1% had metastatic disease. Top three tumor types were breast (20.4%), lymphoma (11.5%), and gastrointestinal (10.8%). The top five concerns for AYA (% AYA, % adults) were fear/worry (56.6, 42.9), understanding of illness (47.6, 41.4), sleep (35.2, 28.9), sadness (34.1, 20.0), and finances (33.8, 15.0). AYA reported higher symptoms of anxiety at baseline (% AYA, % older adults), both moderate (26.0, 19.9) and severe (26.6, 17.1) p < 0.01. Conclusion: Significant differences in psychosocial needs for AYA were seen at diagnosis across multiple domains, specifically, higher emotional, informational, physical, and financial distress. Development of supportive programming geared toward these domains early at diagnosis could benefit this distinct population.

Emotional distress and psychosocial needs in patients with breast cancer in British Columbia: younger versus older adults.

PURPOSE: This study evaluates the prevalence of emotional distress and psychosocial needs in young adult (YA, age 18-39) patients at the time of their breast cancer diagnosis compared to older patients. METHODS: Through a province-wide program, BC Cancer patients complete the PsychoSocial Scan for CANcer-Revised (PSSCAN-R) questionnaire, which screens for the presence of symptoms of anxiety and depression and assesses psychosocial needs using the Canadian Problem Checklist (CPC). The study population comprised all breast cancer patients who completed the questionnaire within 6 months of their cancer diagnosis between 2011 and 2016. Clinical information was retrospectively collected from electronic health records. Univariate and multivariate analyses using the X2, Fisher's exact test, and logistical regression were used to compare patient age groups. RESULTS: The cohort included 10,734 breast cancer patients: median age 62, 4% YA, 99% female, and 96% presented with non-metastatic disease. After adjusting for clinical and demographic variables, YA patients were more likely to report depression (33.6% vs. 25.5%, OR 1.47, p = 0.001) and anxiety symptoms (58.6% vs. 35.7%, OR 2.49, p < 0.001) than older patients. Psychosocial needs regarding work/school (OR 3.79, p < 0.001), intimacy/sexuality (OR 2.82, p < 0.001), and finances (OR 2.78, p < 0.001) were more common among YA than older adults. CONCLUSIONS: After a breast cancer diagnosis, YAs have higher levels of emotional distress compared to older patients. Differences in specific psychosocial needs likely reflect differences in life stage between these age groups. The data suggest that YAs warrant specific attention with respect to early psychosocial assessment and tailored intervention.

Yoga for Health-Related Quality of Life in Adult Cancer: A Randomized Controlled Feasibility Study.

An increase in patient-led uptake of complementary therapies in adult cancer has led to a need for more rigorous study of such interventions and their outcomes. This study therefore aimed to evaluate the feasibility and acceptability of a yoga intervention in men and women receiving conventional treatment for a cancer diagnosis. Prospective, mixed methods feasibility trial allocated participants to receive one of three yoga interventions over a four-week study period. Data collection was completed through online survey of QOL-CA/CS and customized surveys. Fifteen participants were included (11 female) undergoing treatment for breast, prostate, colorectal, brain, and blood and lung cancer. Two participants dropped out and complete qualitative and quantitative data sets were collected from 12 participants and four yoga instructors. Other outcome measures included implementation costs patient-reported preferences for yoga intervention and changes in QOL-CA/CS. Three types of yoga intervention were safely administered in adult cancer. Mixed methods, cost-efficiency, QOL-CA/CS, and evidence-based design of yoga intervention have been used to establish feasibility and patient-preferences for yoga delivery in adult caner. Results suggest that, with some methodological improvements, a large-scale randomized controlled trial is warranted to test the efficacy of yoga for male and female cancer patients. This trial is registered with Clinicaltrials.gov NCT02309112.

Addressing oncofertility needs: views of female cancer patients in fertility preservation.

A total of 41 questionnaires were returned from 64 respondents who consented to receive a questionnaire through the mail. Almost all valued the opportunity to receive consultation to address their fertility concerns and discuss fertility preservation options. Psychological stress, time pressure, and costs were identified as main factors affecting respondents' decision to proceed with in-vitro fertilization to cryopreserve oocytes or embryos. About one third indicated that the discussion of fertility matters was initiated by themselves, their friends, and families rather than their health care providers. The findings have identified several major barriers encountered by female cancer patients when seeking fertility preservation services.