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In Tumor Biology and Cancer Research, It Takes a Village.

December 16, 2022

Edna Cukierman, PhD, Tumor Biology Senior Editor

Few cancer diagnoses are more dire than pancreatic ductal adenocarcinoma (PDAC), which is on its way to becoming the second deadliest cancer in the US. Because the symptoms of PDAC typically do not manifest in the early stages of disease and means for early detection are not very exact (just yet), many patients present with locally advanced or metastatic disease that puts them at immediate risk. Even when PDAC is detected in its early stages, only a portion of cases are surgically resectable—and tumor recurrence can result, even after apparently successful surgical removal. Nonetheless, the pancreatic cancer research community is comprised of a thriving group of highly collaborative individuals with expertise in all aspects of pancreatic biology, cancer, and more. As a result of this, huge strides have been made in the last decade alone, which have greatly increased 5-year survivorship of patients, now reaching double digits, with more discoveries being translated to the clinic each year.

Notably, PDAC’s unique biology sets this solid epithelial tumor apart from other human adenocarcinomas. For example, the PDAC tumor mass, often comprising over half of the malignant lesion, constitutes a cellular chronic scar-like expansion of a fibrous (e.g., collagenous) stromal microenvironment known as desmoplasia. Throughout tumor development and progression, the pancreatic stroma is continuously expanded and remodeled, causing the collapse of blood vessels and rendering poor penetrance of conventional chemotherapies and targeted therapies into the tumor mass. Moreover, the distinctively immunosuppressive desmoplastic expansion also limits the access of hematogenous nutrients and stimulates a reciprocal adaptation of both cancer and stromal cells to alter metabolic exchanges and promote resistance to drugs and radiation. It therefore “takes a village” to both understand the local and systemic underpinnings of PDAC, as well as the holistic aspect of this disease, to translate the village’s discoveries more effectively to the clinic and make meaningful improvements for the PDAC patient community.

To this end, our PDAC village encompasses experts that dedicate their time to improving every aspect of each individual PDAC case—including the evaluation of potential patients at risk for prevention and early detection, psychophysiology, treatment, support, discovery, and more. At the AACR Special Conference on Pancreatic Cancer, which took place in Boston in September 2022, the “village” met. The special conference reflected the village through the representation of all types of experts and stake holders. The sessions dealt with holistic aspects of PDAC—recognizing that each case is unique—and the all-inclusive growth of the village was recognized as both necessary and eminent. As an example, our village highlighted the need for enhanced community outreach for the improvement of equity in health outcomes and the diminishment of clearly noted disparities. With this firmly in mind, we turned the village’s attention towards translation and clinical trial underpinnings, considering the various patient populations in tandem with clinical and biological readouts of tumor plasticity and responses—or lack thereof—to therapeutics. Among these considerations, the village turned its attention to report upon the current challenges in treating locally advanced PDAC, improving upon prevention and interception, and better understanding the unique PDAC microenvironment. Immunobiology and immunotherapy aspects of this disease were central to this discussion and were integrated with emerging insights into the role of metabolism and the microbiome in PDAC biology. The conference highlight, in my opinion, reflects the best qualities of the PDAC village: a spirited “debate” which, rather than devolving into contentious head-butting, presented itself more like an all-encompassing agreement; to not only therapeutically target both tumor and stroma, but also to consider the holistic aspects of this disease, its treatment, and their effects on the wellbeing of patients and their loved ones.

This pancreatic cancer village is the main reason that I am proud to serve on the Cancer Research Communications editorial board as the Senior Editor of the Tumor Biology section. I am also proud to state that our editors have crafted this journal to be adaptable and nimble, and always with the shared goal of communicating valuable, reliable new insights to the entire expanded village: our research community. Hence, my vision for the Tumor Biology Section is indeed to showcase all the aspects of tumor biology, including cellular mechanisms of tumor predisposition, onset, and progression, with a special emphasis on cellular crosstalk and communication. This section emphasizes the fact that cancer is no longer considered a cellular disease, but a whole organ and fully systemic disease rooted in natural occurrences and genetic predispositions, strengthened or discouraged by both macro- and microenvironmental underpinnings.

To that end, this month we have highlighted two recent articles aimed at addressing the complexity of detecting and treating PDAC as our Editors’ Picks. Read on for a summary of these articles, as well as a Q&A with me!

Q&A with the Tumor Biology Senior Editor, Edna “Eti” Cukierman, PhD

  • What was the last book you read?
    • My favorite book ever is “Cien años de soledad” (One Hundred Years of Solitude) by the one and only Gabriel García Márquez.
  • What would you have done if you weren’t in your current occupation?
    • When I was a kid I wanted to be an actress. During high school I stated I will be a chemist/pharmacologist. I was accepted to Veterinary School in Mexico, but I met a great guy and married him, so I moved abroad and thought I would become a vet later…I just have not made it there just yet (LOL).
  • Which scientist (living or dead) do you admire most?
    • Too many to list, but one of my favorite people was Al Knudson—the scientist who coined the “two hit theory.” He invested in me the idea that cells (and tissues) are naturally tumor suppressive, just like stroma, and that harnessing the natural suppression of cells constitutes a highly sought means for effective tumor control.
  • What do you like to do when you are not working on cancer research?
    • I love puzzle games, big Jigsaw puzzles, and many kinds of board games. I also love to go on walks with my guy 😊, and spend time with family and close friends.
  • Who is your favorite musician?
    • Not sure, but I love Achinoam Nini (in Hebrew), classic rock (in English), and modern Latin Rock (in Spanish).
  • What is your favorite food?
    • I have many!!!! I love to eat… my new favorite is French food (bistro type) because I have a Private French Junior Sous Chef (my younger son). I also love Mexican food (but only authentic), and new cuisine with inventive multicultural flares.

 

December 2022 Editors’ Picks:

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor that suffers from poor outcomes and limited therapeutic options, particularly with regard to effective targeted therapies. Despite improvements in patient outcomes over the last ten years, long term survival remains poor and better methods of detection and treatment are urgently needed. To address these clinical challenges, Hidalgo and colleagues performed a preclinical to Phase Ib study of the CDK4/6 inhibitor Palbociclib in combination with nab-paclitaxel in patient-derived PDAC xenografts followed by a dose-escalation study in human patients with PDAC. While the regimen showed promising preclinical activity and was well-tolerated by patients, it failed to reach the prespecified efficacy threshold in the clinical phase of the study. Further analysis of the data suggested that concurrent administration of chemotherapy with CDK4/6 inhibition may have blunted the effect of both, suggesting that administration of palbociblib subsequent to chemotherapy may yield a stronger effect via disruption of DNA damage repair pathways.

The results of the palbociclib/nab-paclitaxel trial underscore the intractable nature of PDAC and speak to the need for better biomarkers for both patient selection in clinical trials, as well as earlier detection of disease. To that end, Kane and colleagues performed a systematic review and meta-analysis of previously reported biomarkers for PDAC, including CA-19-9, TIMP-1, CEA, and CA125. After assessing the performance of multi-biomarker panels both with and without CA-19-9 via multivariate analyses, the authors find that the integration of many biomarkers into a panel test was superior to single biomarkers. While CA-19-9—the most commonly used single biomarker for PDAC—had limited efficacy alone, its inclusion in multi-biomarker panels resulted in the best predictive potential. Taken together, these two studies speak to the importance of carefully designed, multi-disciplinary, and collaborative efforts to most effectively advance PDAC patient outcomes.

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