Identification of Small Molecule Inhibitors of PPM1D Using a Novel Drug Discovery Platform.

Protein phosphatase, Mg2+/Mn2+ dependent 1D (PPM1D), is a serine/threonine phosphatase that is recurrently activated in cancer, regulates the DNA damage response (DDR), and suppresses the activation of p53. Consistent with its oncogenic properties, genetic loss or pharmacologic inhibition of PPM1D impairs tumor growth and sensitizes cancer cells to cytotoxic therapies in a wide range of preclinical models. Given the therapeutic potential of targeting PPM1D specifically and the DDR and p53 pathway more generally, we sought to deepen our biological understanding of PPM1D as a drug target and determine how PPM1D inhibition differs from other therapeutic approaches to activate the DDR. We performed a high throughput screen to identify new allosteric inhibitors of PPM1D, then generated and optimized a suite of enzymatic, cell-based, and in vivo pharmacokinetic and pharmacodynamic assays to drive medicinal chemistry efforts and to further interrogate the biology of PPM1D. Importantly, this drug discovery platform can be readily adapted to broadly study the DDR and p53. We identified compounds distinct from previously reported allosteric inhibitors and showed in vivo on-target activity. Our data suggest that the biological effects of inhibiting PPM1D are distinct from inhibitors of the MDM2-p53 interaction and standard cytotoxic chemotherapies. These differences also highlight the potential therapeutic contexts in which targeting PPM1D would be most valuable. Therefore, our studies have identified a series of new PPM1D inhibitors, generated a suite of in vitro and in vivo assays that can be broadly used to interrogate the DDR, and provided important new insights into PPM1D as a drug target.

PPM1D modulates hematopoietic cell fitness and response to DNA damage and is a therapeutic target in myeloid malignancy.

PPM1D encodes a phosphatase that is recurrently activated across cancer, most notably in therapy-related myeloid neoplasms. However, the function of PPM1D in hematopoiesis and its contribution to tumor cell growth remain incompletely understood. Using conditional mouse models, we uncover a central role for Ppm1d in hematopoiesis and validate its potential as a therapeutic target. We find that Ppm1d regulates the competitive fitness and self-renewal of hematopoietic stem cells (HSCs) with and without exogenous genotoxic stresses. We also show that although Ppm1d activation confers cellular resistance to cytotoxic therapy, it does so to a lesser degree than p53 loss, informing the clonal competition phenotypes often observed in human studies. Notably, loss of Ppm1d sensitizes leukemias to cytotoxic therapies in vitro and in vivo, even in the absence of a Ppm1d mutation. Vulnerability to PPM1D inhibition is observed across many cancer types and dependent on p53 activity. Importantly, organism-wide loss of Ppm1d in adult mice is well tolerated, supporting the tolerability of pharmacologically targeting PPM1D. Our data link PPM1D gain-of-function mutations to the clonal expansion of HSCs, inform human genetic observations, and support the therapeutic targeting of PPM1D in cancer.

Investigation of the Readability and Reliability of Online Health Information for Cancer Patients During the Coronavirus Pandemic.

For cancer patients undergoing treatment who may be at higher risk of COVID-19, access to high-quality online health information (OHI) may be of particular importance amidst a plethora of harmful medical misinformation online. Therefore, we assessed the readability and quality of OHI available for various cancer types and treatment modalities. Search phrases included "cancer radiation COVID," "cancer surgery COVID," "cancer chemotherapy COVID," and "cancer type COVID," for the fourteen most common cancer types (e.g., "prostate cancer COVID" and "breast cancer COVID"), yielding a total of 17 search phrases. The first 20 sources were recorded and analyzed for each keyword, yielding a total of 340 unique sources. For each of these sources, the approximate grade level required to comprehend the text was calculated as a mean of five validated readability scores; subsequently, for the first ten results of each search, the DISCERN tool was manually used to assess quality. Search terms were translated into Spanish and French, and a quality assessment using the Health on the Net Code (HONcode) accreditation was conducted. The median grade level readability for all sources was 13 (IQR 11-14). Median DISCERN scores for the 170 sources assessed were 55 out of 75, suggesting good quality. OHI with quality scores below the median DISCERN score had a median readability of 12.5 (IQR 11-14) grade reading level vs 14 (IQR 12-17) for those above the median DISCERN score (T-test P < 0.0001). Percentages of HONcode-accredited websites were 34.9%, 39.9%, and 38.6% for English, Spanish, and French OHI, respectively. We conclude that efforts are needed to make high-quality OHI available at the appropriate reading level for patients with cancer; such efforts may contribute to the alleviation of disparities in access to healthcare information.