Global Cancer Institute

Targeted therapies eliminate cancer cells by inhibiting oncogenic signaling; however, tumor cells often evade cytotoxicity through proteomic and epigenetic reprogramming that enables survival. These adaptive responses may create collateral cellular stresses, such as DNA damage, that can be therapeutically exploited. When unresolved, DNA damage leads to chromosomal instability (CIN), a potential source of vulnerability. Whether KRAS inhibition induces DNA damage or CIN in KRAS -mutant non-small cell lung cancer (NSCLC) has not been established. Here, we show that the KRAS G12C inhibitor LY3499446 induces CIN in KRAS -mutant NSCLC cell lines. A targeted compound screen revealed that the extent of CIN induction by KRAS G12C inhibition strongly correlates with therapeutic synergy with the selective Aurora kinase A inhibitor LSN3321213. Mechanistically, KRAS G12C inhibition stabilizes cyclin B1 during mitosis through activation of mitotic ATR/ATM signaling. In the presence of Aurora Kinase A inhibition, cyclin B1 stabilization delays mitotic exit and diverts cell fate from mitotic slippage or division toward mitotic catastrophe. Together, our findings identify CIN as a predictive marker of response to combined KRAS G12C and Aurora Kinase A inhibition, providing mechanistic rationale to enhance the therapeutic window of AURKA inhibitors when used with targeted therapies.

Cancer is a systemic manifestation of aberrant cell cycle activity and dysregulated cell growth. Genetic mutations can determine tumor onset by either augmenting cell division rates or restraining normal controls such as cell cycle arrest or apoptosis. As a result, tumor cells not only undergo uncontrolled cell division but also become compromised in their ability to exit the cell cycle accurately. Regulation of cell cycle progression is enabled by specific surveillance mechanisms known as cell cycle checkpoints, and aberrations in these signaling pathways often culminate in cancer. For instance, DNA damage checkpoints, which preclude the generation and augmentation of DNA damage in the G1, S, and G2 cell cycle phases, are often defective in cancer cells, allowing cell division in spite of the accumulation of genetic errors. Notably, tumors have evolved to become dependent on checkpoints for their survival. For example, checkpoint pathways such as the DNA replication stress checkpoint and the mitotic checkpoint rarely undergo mutations and remain intact because any aberrant activity could result in irreparable damage or catastrophic chromosomal missegregation leading to cell death. In this review, we initially focus on cell cycle control pathways and specific functions of checkpoint signaling involved in normal and cancer cells and then proceed to examine how cell cycle control and checkpoint mechanisms can provide new therapeutic windows that can be exploited for cancer therapy. SIGNIFICANCE STATEMENT: DNA damage checkpoints are often defective in cancer cells, allowing cell division in spite of the accumulation of genetic errors. Conversely, DNA replication stress and mitotic checkpoints rarely undergo mutations because any aberrant activity could result in irreparable damage or catastrophic chromosomal missegregation, leading to cancer cell death. This review focuses on the checkpoint signaling mechanisms involved in cancer cells and how an emerging understanding of these pathways can provide new therapeutic opportunities for cancer therapy.

BackgroundCervical cancer is preventable with vaccination and early detection and treatment programs. However, in order for these programs to work as intended, stigma related to HPV and cervical cancer must be understood and addressed. We explored pre-existing stigma associated with HPV and cervical cancer in the public healthcare system of a low-resource setting prior to implementation of an HPV screen-and-treat program.MethodsThis study conducted thematic analysis of data collected during implementation of a novel HPV screen-and-treat system for cervical cancer early detection and treatment in Iquitos, Peru. We included 35 semi-structured interviews (19 health professionals, 16 women with cervical precancer or cancer), eight focus groups (70 community women), one workshop (14 health professionals), 210 counseling observations (with 20 nurse-midwives), and a document review. We used the Socio-Ecological Model to organize the analysis.ResultsWe identified three main themes: 1. the implication that women are to blame for their HPV infection through characterizations of being easy or promiscuous, 2. the implication that men are to blame for women’s HPV infections through being considered careless or unfaithful, 3. HPV is shameful, embarrassing, and something that should be hidden from others. Consequently, in some cases, women refrained from getting screened for HPV. These themes were seen at the individual level among women, relationship level among women, men, and family members, community level among healthcare staff, and societal level within components of cervical cancer guidelines and male chauvinism.ConclusionsCervical cancer early detection and treatment programs in limited resource settings must address stigma entrenched throughout the entire healthcare system in order to sustainably and successfully implement and scale-up new programs. Interventions to tackle this stigma can incorporate messages about HPV infections and latency to lessen the focus on the influence of sexual behavior on HPV acquisition, and instead, promote screening and treatment as paramount preventative measures.

Patient navigation (PN) is a community-based service delivery intervention designed to promote access to timely diagnosis and treatment of cancer and other chronic diseases by eliminating barriers to integral care. Considering the complex difficulties in accessing treatment and the positive results of PN in high-income countries, our group decided to evaluate this tool to improve radiotherapy (RT) access in the public system in Brazil. This pilot study took place in a public school hospital, with a historical cohort as the control arm. The primary endpoint was the time from histologic diagnosis and RT initiation among cancer patients receiving RT with curative intent in a PN program. The secondary objectives were the following time frames: referral to the first consultation by the RT team; first consultation up to RT beginning; RT beginning to RT end; referral to the end of RT and identifying/describing obstacles to the treatment; and assessing patient satisfaction with PN program. A total of 124 patients were included in the retrospective arm and 73 in the navigation arm. Most had the loco-regionally advanced disease from the esophagus, head/neck, and rectum. PN decreased the median time from the biopsy result to the beginning of RT from 108 to 74days (p < 0.001). PN reduced the time between biopsy results and referral to RT (53 to 40.5days, p = 0.011), between the referral and the first consultation in the RT (25 to 13days, p < 0.001), and between the referral to the end of the RT (98 to 78days, p < 0.003). Proper identification of barriers, especially in a low-resource setting, is mandatory to guide PN programs in LMICs. In an oncological context of socioeconomic vulnerability, PN is a financially viable and efficient tool to optimize access to timely RT.

The PRECE is a model predicting the risk of extracapsular extension (ECE) of prostate cancer: it has been developed on more than 6000 patients who underwent robotic radical prostatectomy (RARP) at the Global Robotic Institute, FL, USA. Up to now, it is the single tool predicting either the side and the amount of ECE. The model has a free user-friendly interface and is made up from simple and available covariates, namely age, PSA, cT, GS and percent of positive core, the latter topographically distributed within the prostate gland. Despite the successful performance at internal validation, the model is still lacking an external validation (EV). The aim of the paper is to externally validate the PRECE model on an Italian cohort of patients elected to RARP. 269 prostatic lobes from 141 patients represented the validation dataset. The EV was performed with the receiver operating characteristics (ROC) curves and calibration, to address the ability of PRECE to discriminate between patients with or without ECE. Overall, an ECE was found in 91 out of the 269 prostatic lobes (34%). Twenty-five patients out of pT3 had a bilateral ECE. The ROC curve showed an AUC of 0.80 (95% CI 0.74-0.85). Sensitivity and specificity were 77% and 69%, respectively. The model showed an acceptable calibration with tendency towards overestimation. From the current EV, the PRECE displays a good predictive performance to discriminate between cases with and without ECE; despite preliminary, outcomes may support the generalizability of the model in dataset other than the development one.

Abstract Chimeric Antigen Receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies. Approximately half of patients with refractory large B-cell lymphomas achieve durable responses from CD19-targeting CAR-T treatment; however, failure mechanisms are identified in only a fraction of cases. To gain novel insights into the basis of clinical response, we performed single-cell transcriptome sequencing of 105 pre- and post-treatment peripheral blood mononuclear cell samples, and infusion products collected from 32 individuals with high-grade B cell lymphoma treated with either of two CD19 CAR-T products: axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel). Expansion of proliferative memory-like CD8 clones was a hallmark of tisa-cel response, whereas axi-cel responders displayed more heterogeneous populations. Elevations in CAR-T regulatory cells (CAR-Tregs) among non-responders to axi-cel were detected, and these populations were capable of suppressing conventional CAR-T cell expansion and driving late relapses in an in vivo model. Our analyses reveal the temporal dynamics of effective responses to CAR-T therapy, the distinct molecular phenotypes of CAR-T cells with differing designs, and the capacity for even small increases in CAR-Tregs to drive relapse.

Abstract Purpose: Persons living with HIV have elevated risks of HPV-related cervical, anogenital, and oropharyngeal cancers. Yet, research on optimization and implementation of prevention interventions (prophylactic HPV vaccination, cervical and anogenital cancer screening and triage, and precancer therapeutics) for HPV-related cancers among persons living with HIV has been limited. With a goal to expand this evidence, and building on strong academic research partnerships developed for HIV research between institutions in the US and the Latin American and the Caribbean (LAC) region, the US National Cancer Institute (NCI) initiated ULACNet, a new Cooperative Agreement clinical trials network in 2019. Methods: ULACNet comprises of three Partnership Centers each led by US-based institutions (University of California San Francisco, Weill Medical College of Cornell University, and Fred Hutchinson Cancer Research Center), working collaboratively with US and LAC institutions and with the NCI to develop and conduct multicenter prevention clinical trials focused on filling key scientific gaps and evaluating novel interventions. Results: ULACNet encompasses six countries (US, Mexico, Puerto Rico, Brazil, Peru, and Dominican Republic), twenty partner institutions, and over 100 collaborating scientific investigators, clinical and public health practitioners, research staff, and patient advocates. ULACNet will collaboratively conduct nine prevention clinical trials (two prophylactic HPV vaccine trials in adults and perinatally-HIV infected adolescents, three trials for clinical validation of molecular biomarkers and imaging technologies for screening and triage, two candidate HPV therapeutic vaccine trials, and two trials of topical therapeutic agents). Facilitation across network partners is achieved via a Coordinating Committee and three Working Groups (focused on HPV testing and screening, precancer treatment, and recruitment and retention activities). Conclusion: ULACNet seeks to leverage established academic global health partnerships to conduct high quality collaborative clinical trials to inform clinical practice and ultimately reduce the burden of highly preventable HPV-related cancers in persons living with HIV worldwide. Citation Format: Emma Brofsky, Margaret House, Brandy Heckman-Stoddard, Mostafa Nokta, Satish Gopal, Vikrant Sahasrabuddhe. Development of International Cancer Research Partnerships Through the NCI US-Latin American-Caribbean HIV/HPV-Cancer Prevention Clinical Trials Network (ULACNet) [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 20.