Wenrui Duan Ph.D.

Recipient of the LUNGevity Foundation/Joan’s Legacy Research Grant. Funded equally by Joan's Legacy and the LUNGevity Foundation.

Lay Description

75-85% of lung cancers are categorized as non-small cell cancers. p53 mutations are reported in 50-60% of non-small cell lung cancers and in up to 90% of small cell tumors, thus p53 represents a common mutation in this malignancy. Preclinical studies have shown that restoring wild type p53 function leads to regression of cancers, supporting the notion of treating human cancers by way of pharmacological reactivation of p53.

The novel small molecule PRIMA-1(p53-dependent reactivation and induction of massive apoptosis) has been shown to induce apoptosis in human tumor cells containing mutant p53 by restoration of the tumor suppressor function of p53. We investigated the effects of PRIMA-1 in apoptosis using human lung cancer cell lines and found that this compound could induce apoptosis in lung cancer cells containing mutant p53, but was less toxic to the cells containing wild type p53. Because most normal lung cells contain wild type p53, the PRIMA-1 is expected to be much less toxic to normal lung cells compared to cancer cells.

We have previously developed a line of lung specific mutant p53 transgenic models, which develop spontaneous non-small cell lung cancers. Here we propose to treat these lung tumor bearing models with PRIMA-1 either as a single agent or in combination with cisplatin. Further understanding the role of PRIMA-1 in induction of apoptosis in spontaneous lung cancer containing mutant p53 gene may lead.

Scientific Abstract

P53 mediates tumor suppression by activating the transcription of multiple genes specifically involved in cell cycle regulation, apoptosis, and genomic stability. Its activation responds to various stress signals. Mutant p53 proteins fail to bind DNA and transactivate p53 target genes that mediate cell cycle arrest or apoptosis. Mutation of the p53 tumor suppressor gene is the most frequently reported genetic defect in human lung cancer, with mutations observed in greater than 50% of non-small cell lung cancer. The frequent mutation of p53 and loss of p53 function in tumors make mutant p53 a prime target for pharmacological therapeutic interventions in cancer. The novel small molecule PRIMA-1 (p53-dependent reactivation and induction of massive apoptosis) has been shown to induce apoptosis in human tumor cell lines containing mutant p53 by restoration of the tumor suppressor function of p53. This is believed to be mediated by a change in the conformation of mutated p53 protein, restoring DNA binding and activation of p53 target genes. We investigated this compound in several human lung cancer cell lines A549 (wild type p53), H23 (mutant p53, 246I), H211 (mutant p53, 248Q), and H1155 (mutant p53, 273H). We found that PRIMA-1 selectively induced apoptosis in lung cancer cells containing mutant p53 (H23, H211 and H1155), but was less toxic to the cells containing wild type p53 (A549). In addition, we found that PRIMA-1 up-regulates micro RNA 34s to promote apoptosis in the lung cancer cells containing mutant p53.

We have previously developed a line of transgenic models in which a frequent mutant p53(273H) is expressed in a lung specific manner through the control of the surfactant C (SPC) promoter. These models develop a single lung tumor with histological characteristics of human adenocarcinomas. Here we propose to treat these lung tumor bearing models with PRIMA-1 either as a single agent or in combination with cisplatin. We hypothesize that: 1. the small molecule PRIMA-1 can be used to restore the p53 function to mutant p53 leading to regression of lung cancers in the SPC-p53/273H transgenic models. 2. PRIMA-1 can induce apoptosis in the non small cell lung cancers containing mutant p53(273H). 3. Prima-1 can up-regulate tumor suppressor micro RNA 34 family to induce apoptosis. 4. Combination of PRIMA-1 with cisplatin will increase the response of lung tumors to anticancer therapy.

The aim of this study is to uncover the potential role of PRIMA-1 in inducing apoptosis in spontaneous non small cell lung cancers. We are especially interested in the relationship between PRIMA-1 and micro RNAs in the apoptotic pathway in spontaneous non small cell lung cancers. Knowledge obtained from this study may help guide therapeutic strategies to develop effective strategies for p53-related pharmacological therapeutic intervention in patients with lung cancers.