Debi & Gary Fournier Translational Research Program for Cervical Cancer
Cervical cancer is a leading cause of death among women in the world. A “one-size-fits-all” approach of drug development and treatment has left mortality rates essentially unchanged over the last 30 years. The improvements in basic sciences have not translated into better treatment outcomes for patients diagnosed with cervical cancer. We believe that a detailed understanding of the molecular heterogeneity and of the genes and pathways that are altered in evolving subgroups is needed to direct the clinical application of an unprecedented volume of new therapeutics with improved accuracy. The pioneering nature of our research is the understanding that cervical cancer can be broken out into distinct molecular subtypes which each have to be treated differently.
To date, the number of efficacious drugs approved by regulatory authorities remains disappointingly low, and actually only one new drug has been approved for the treatment of cervical cancer in the last 30 years. Moreover, the number of clinical trials of targeted therapies in patients with cervical cancer is limited and the results, although encouraging, reveal limited effects on survival.
Although there are many reasons for this lack of success in the development of new treatments for patients diagnosed with cervical cancer, at least some result from a poor understanding of how best to use a drug in patients, as opposed to the generation of compounds that have inadequate pharmaceutical properties. This impediment is in part related to the absence of comprehensive molecular profiling data on cervical cancers and points in turn to an imprecise (or incomplete) use of model systems during the preclinical development of a drug.
The main drug development strategy in cervical cancer that is still being pursued in 2017 is using the traditional empiric drug development approach in which a new targeted agent is broadly added to an existing standard chemotherapy regimen. New targeted agents are being tested in unselected cervical cancer patients regardless of whether the pathway being targeted is ether activated or even altered. Historically, if a new targeted agent did not achieve a response rate of 20% or higher in unselected patients, further drug development was not pursued. This approach did not recognize the potential of many targeted therapies that require the presence/alteration/activation of a drug specific target (e.g. treating the wrong patient with the right drug). In contrast to the advances made in other solid tumors, to the best of our knowledge, no routine molecular diagnostic tests have been introduced to guide personalized cervical cancer treatment.
The Cancer Genome Atlas Research Network (TCGA) recently published the most comprehensive, multi-omic molecular characterization of cervical cancers performed to date. The data reveal novel disease subtypes, and provide new insights into the pathogenesis of cervical cancer. Importantly, the information obtained has potentially major clinical implications and represents an unprecedented opportunity to tailor novel treatments to the evolving molecular subgroups of patients diagnosed with cervical cancer.
In our efforts to develop innovative, new and novel treatment rationales for women diagnosed with cervical cancer, with support through the Debi & Gary Fournier Cervical Cancer Research Fund, we are establishing a molecularly characterized, robust, large-scale cervical cancer cell line panel which comprehensively reflects the molecular heterogeneity of the disease that has been carefully characterized in the recent TCGA study on cervical cancer. A major and fundamentally flawed assumption in preclinical drug development has traditionally been that if you have three to four cell line examples of a given cancer, you have that particular disease “covered” in the research platform. It is now known that the molecular diversity within a given histology can be quite broad. If you have only three to four cell lines representing a given disease in your research panel, you may either completely miss or grossly over-interpret critical response phenomena when screening for drug activity.
We will then perform broad preclinical testing of a large number of directed inhibitors to develop tailored treatment rationales. Additional in depth studies will be performed for front-running compounds. Moreover, beneficial combination therapies will be identified by performing formal drug interaction studies to identify synergistic drug combinations. These goals will be accomplished by applying an integrated and combined research approach that has been successfully implemented in the UCLA Health Jonsson Comprehensive Cancer Center (JCCC)/Translational Oncology Research Laboratory (TORL) over the last years for more common cancers such as breast, lung and ovarian cancer or malignant melanoma. These past research efforts, in fact, led to the FDA approval of a number of new agents for patients diagnosed with cancer. Examples where the JCCC has made the most critical contributions are: Trastuzumab (Herceptin™), palbociclib (Ibrance™), pembrolizumab, (Keytruda™), and rucaparib (Rubraca™) using this integrated drug development approach.