Metabolic Reprogramming to Improve Cancer Outcomes

Dr. Simone’s laboratory has contributed significantly to studying the effect of dietary behavioral interventions to induce metabolic reprogramming to improve cancer outcomes and response to cytotoxic therapy. The lab demonstrated for the first time that caloric restriction (CR) modifies microRNA expression (Ørom et al., Cell Cycle, 2012). Dr. Simone’s laboratory was the first to discover that caloric restriction (CR) improves radiation sensitivity (Saleh et al., Cell Cycle, 2013), which she then translated directly to an investigator- initiated clinical trial (IIT) using a dietary intervention during radiation for early stage breast cancer patients (NCT01819233). Here they found that patients undergoing radiation therapy are able to adhere to dietary interventions and their miR-21 decreases. Taking this observation back to the laboratory, they created a novel model (miR-21 knockout murine model) and have demonstrated its unique phenotype of both radiation sensitivity in vivo (Puccetti et al., IJROBP 2019) and role in cancer initiation and metastases (Dan et al., Cancers 2021). To further expand their clinical understanding of the role of miR-21 and metabolic reprogramming, they are now performing a randomized IIT clinical trial (NCT04959474) administering preoperative radiation to the partial breast with patients being randomized to a dietary modification or usual diet to understand the impact on the tumor itself. Understanding the mechanistic link of miR-21 on tumor progression and radiation sensitivity, they performed Dr. Simone’s second IIT to determine the miR-21 change when caloric restriction is done before definitive oncologic surgery for patients with endometrial, prostate, and breast cancer (NCT02983279). This trial not only found that miR-21 decreased with CR but also that metabolic reprogramming is feasible in short time periods in prostate cancer which led to her collaboration on a U54 ROBIN grant (U54CA273956). In addition, she has received funding to expand these findings and assess metabolic reprogramming to improve radiation response in lung cancer (R01CA232587). The laboratory also found improved physiologic response of the primary tumor in vivo when CR was combined with chemotherapy, which was translated directly to their third IIT clinical trial (NCT02827370). Her laboratory also investigated the role of microRNAs in the ability of CR to decrease metastatic disease burden via control of the ECM (Jin et al., Breast Cancer Res Treat, 2014; Simone et al., Cell Cycle, 2016). To expand on these findings the lab is now investigating the role of CR given concurrently with radiation for brain metastases through their R01CA227479. Their findings demonstrate improved intracranial control and they have just received funding to translate this into their next IIT clinical trial. 

Novel Research to Decrease Treatment-Related Toxicity

In her clinical role, Dr. Simone has observed the devastating effects of long- term toxicity from radiation. The Simone lab also investigates radiation treatment related toxicity and the use of metabolic interventions to decrease toxicity from cytotoxic therapy. The lab first investigated preclinical models of toxicity and demonstrated for the first time that microRNAs modulating inflammation are in part responsible for radiation- induced fibrosis (1ZIABC010873). Dr. Simone performed a pilot trial to determine if Pirfenidone, a novel regulator of cytokine gene expression, had the potential to ameliorate established radiation-induced fibrosis in patients, and in a national clinical trial NRG 1014, have assessed various radiation regimens to minimize toxicity from re-irradiation for breast cancer. R01 using diet to improve radiation for brain metastases shows that diet decreases neurocognitive decline. The lab has expanded our research minimizing cardiac and skin toxicity.

Identifying Health Disparities & Creating Interventions to Mitigate Them

Dr. Simone’s first in- human clinical trials, using caloric restriction for breast cancer patients undergoing radiation therapy or chemotherapy were able to enroll 50% African American women. While the lab noted that all of our patients had optimal compliance with dietary interventions, they noted that baseline characteristics and inflammatory markers were significantly more adverse in Black compared to White patients. The lab now has a health disparities supplement to investigate these differences they previously noted (S-R01CA227479)  has started the EXIST IIT clinical trial to identify if social determinants or patient distress is driving inflammation in Black patients who are 40% more likely to die compared to White patients. Since these differences are not unique to breast cancer patients, the ROBIN grant will assess the metabolic and immune factor differences between Black and White patients (U54CA273956). 

Additionally, Dr. Simone works to advocate for patients who experience health disparities and has clinical trials open to identify concerns of patients with cancer screening or disparities in outcome in the geriatric oncology (Lombardo et al. J Geriatr Oncol 2023), the Chinatown population, and sexual and gender minority (SGM) populations (Lombardo et al. Cancer Causes Control 2022, Lombardo et al. NEJM 2020). To further her work in helping to work towards equity in cancer screening for SGM populations, Dr. Simone received the P30CA056036. Finally, Dr. Simone works to identify gender disparities in the physician workforce to create equitable environments for all physicians to work (Roubinov et all J Women’s Health 2023, and Andersen et al Elife 2020)..