Improving Antibody-Tubulysin Conjugates through Linker Chemistry and Site-Specific Conjugation.

Tubulysins have emerged in recent years as a compelling drug class for delivery to tumor cells via antibodies. The ability of this drug class to exert bystander activity while retaining potency against multidrug-resistant cell lines differentiates them from other microtubule-disrupting agents. Tubulysin M, a synthetic analogue, has proven to be active and well tolerated as an antibody-drug conjugate (ADC) payload, but has the liability of being susceptible to acetate hydrolysis at the C11 position, leading to attenuated potency. In this work, we examine the ability of the drug-linker and conjugation site to preserve acetate stability. Our findings show that, in contrast to a more conventional protease-cleavable dipeptide linker, the ß-glucuronidase-cleavable glucuronide linker protects against acetate hydrolysis and improves ADC activity in vivo. In addition, site-specific conjugation can positively impact both acetate stability and in vivo activity. Together, these findings provide the basis for a highly optimized delivery strategy for tubulysin M.

Novel Auristatins with High Bystander and Cytotoxic Activities in Drug Efflux-positive Tumor Models.

Auristatins, a class of clinically validated anti-tubulin agents utilized as payloads in antibody-drug conjugates, are generally classified by their membrane permeability and the extent of cytotoxic bystander activity on neighboring cells after targeted delivery. The drugs typically fall within two categories: membrane permeable monomethyl auristatin E-type molecules with high bystander activities and susceptibility to efflux pumps, or charged and less permeable monomethyl auristatin F (MMAF) analogs with low bystander activities and resistance to efflux pumps. Herein, we report the development of novel auristatins that combine the attributes of each class by having both bystander activity and cytotoxicity on multidrug-resistant (MDR+) cell lines. Structure-based design focused on the hydrophobic functionalization of the N-terminal N-methylvaline of the MMAF scaffold to increase cell permeability. The resulting structure-activity relationships of the new auristatins demonstrate that optimization of hydrophobicity and structure can lead to highly active free drugs and antibody-drug conjugates with in vivo bystander activities.

Masculinity, Racism, Social Support, and Colorectal Cancer Screening Uptake Among African American Men: A Systematic Review.

Colorectal cancer (CRC) is highly preventable when CRC screening is utilized, yet CRC screening completion among African American men is relatively low and their mortality rates remain 50% higher juxtaposed to their White counterparts. Since a growing body of literature indicates masculinity, racism, and social support each have strong influences on CRC screening uptake, this systematic review examined the connections between these three sociocultural factors and CRC screening uptake among African American men. Potential studies were retrieved from MEDLINE, CINAHL, EMBASE, and PsycINFO. Cited reference searching for the final sample was employed to identify and assess additional studies for inclusion using Scopus. The methodological quality of the reviewed evidence was also evaluated. Nineteen studies met inclusion/exclusion criteria. Thirteen studies employed nonexperimental research designs; a quasi-experimental design was present in four, and two utilized experimental designs. Studies were published between 2000 and 2014; the majority between 2009 and 2013. Social support was most frequently addressed (84%) while masculinity and racism were equally studied with paucity (11%) for their influence on CRC screening. After evaluating conceptual and methodological characteristics of the studies, 42% fell below average in quality and rigor. The need for increased attention to the sociocultural correlates of CRC screening for African American men are highlighted in this systematic review, and important recommendations for research and practice are provided. Alongside a call for more rigorous research, further research examining the influence of masculinity and racism on CRC screening completion among African American men is warranted.

Fatalistic Beliefs About Cancer Prevention Among Older African American Men.

OBJECTIVES: Evidence suggests that minority groups are more likely to exhibit fatalistic beliefs about cancer prevention (FBCP), which are defined as confusion, pessimism, and helplessness about one's ability to prevent cancer. This study examines the socioeconomic and psychosocial predictors of FBCP among older African American men (AAM). METHODS: AAM (N = 1,666) enrolled in Medicare and participating in a longitudinal study on patient navigation were surveyed. Measures included three FBCP constructs, namely demographic items and physical and mental health variables. Binary logistic regression was performed. RESULTS: The average participant was 73.6 years old; 76.5% felt helpless, 44.2% were confused, and 40.7% were pessimistic about the ability to prevent cancer. As education increased, so did all three FBCP. Being downhearted was predictive of confused and helpless beliefs. DISCUSSION: It is critical for health practitioners to understand how psychosocial and economic challenges influence beliefs that may impede cancer prevention efforts for older AAM.

Social epidemiology: a tool for examining prostate cancer early-detection decision making among older African American men.

The article explores the disparate burden of prostate cancer among older African American men, and this population's minimal use of cancer early-detection strategies. Social epidemiology is introduced as an emerging field that studies the social context of disease with an emphasis on how macrostructural forces and human interactions affect population health. A conceptual model is presented as a social epidemiological tool for investigating complex health and social issues and developing culturally relevant programs and interventions based on empirical findings. The model is then applied to the problem of prostate cancer early-detection decision making among older African American men.

Factors Associated With Cancer Family History Communication Between African American Men and Their Relatives.

African American men bear a disproportionately high burden from cancer in the U.S. The American Cancer Society reports that for all cancer sites combined, African American men are 32% more likely to die than white men (American Cancer Society, 2011). Having a family history of cancer elevates an individual's risk for the disease and should inform decision-making around the use of specific cancer screening tests as well as earlier onset and frequency of cancer screening. Adult African American men who attended an annual hospital-based community health fair in the Midwest which targeted minority men, were approached to complete a paper-based survey. Participants were asked "have you ever talked with any of your relatives about your family history of cancer (about any members of your family who have been diagnosed with cancer)?" Predictors were evaluated using bivariate analysis and logistic regression; they included socio-demographic, health access, health behavior, health status, and communication variables. Participants were 558 African American men with a mean age of 54 years old. African American men were most likely to have ever discussed their family history of cancer with a relative if they had specific knowledge of their family history of cancer and if they had ever talked to a physician about their family history of cancer. For African American men with a familial predisposition to cancer, further examination of barriers and facilitators to discussion with relatives, specifically those related to health access and knowledge, is warranted.

Social Determinants Associated with Colorectal Cancer Screening in an Urban Community Sample of African-American Men.

BACKGROUND: African-American men are disproportionately burdened with colorectal cancer (CRC). Research is scarce on the social determinants that may influence CRC screening as the primary strategy for early detection among African-American males. METHODS: African-American men over the age of 18 years (n = 558) were recruited from a community health fair and anonymously surveyed about their health and cancer screening behaviors. A social ecological theoretical framework was utilized to identify intrapersonal, interpersonal, organizational, and community predictors of CRC screening, which may be associated with social determinants of health and health behaviors. Analysis included correlations and logistic regression. RESULTS: The mean age of participants was 54.3 years with 85.8% of men being over 40 years of age. Regarding CRC screening: 50.5% (n = 282) of African-American male participants had received any type of CRC screening at any time. Positive predictors of CRC screening included: health insurance status, older age, having spoken with a health provider about family cancer risk, and having a regular doctor. However, employment status and poor self-rated health were negative predictors of the outcome. CONCLUSIONS: Social determinants of health, such as healthcare access and interactions with health systems, along with employment play a critical role in facilitating CRC screening completion in high-risk underserved populations such as African-American men.