Project Details
Description
There is an urgent need to identify new and effective drugs for small cell lung cancer (SCLC), a tumor
characterized by aggressive growth, early metastases, and a 5-year survival rate of less than 2%. While it is
initially chemosensitive, with 70% response rates to first-line therapy of cisplatin plus etoposide, most patients
relapse after initial therapy with drug-resistant tumors. Dozens of new drugs have been tested for activity in
SCLC over the decades, including more than 40 agents that have failed in phase III trials. None of the targeted
drugs used in non-small cell lung cancer or other solid tumors are effective in SCLC.
An outstanding feature of SCLC is the near uniform bi-allelic genetic inactivation of RB1 and TP53.
However, since genetically inactivated RB1 and TP53 cannot be reactivated nor is it clinically feasible to
reintroduce them into SCLC cells, this defining genetic feature has not led to treatment strategies for SCLC. In
this grant, we will test the hypothesis that inhibiting a downstream target of Rb1 can re-establish the tumor
suppressor and pro-apoptotic actions that were lost when Rb1 was inactivated.
In preliminary studies, we found that modulation of only one downstream target of Rb1, the E3 ubiquitin
ligase SCFSkp2/Cks1 (Skp2), can dramatically block the pro-tumorigenic consequences of the loss of Rb1, and
induce Rb1-Skp2 synthetic lethal apoptosis in SCLC. This is due to the role Rb1 and Skp2 play in the
regulation of p27 (CDKN1B), whereby the loss of Rb1 leads to the Skp2-mediated ubiquitination and
degradation of p27 and the subsequent loss of cell cycle regulation. Most critically, we have identified active,
small molecule Skp2 inhibitors to specifically target this vulnerability.
The specific aims are: 1) To determine the role of the Cks1-Skp2 interaction in Rb1 and p53 deletion-
induced SCLC. If the role is found to be essential, we will have identified another target to inhibit Skp2-medited
p27 ubiquitination. Since some human SCLCs with p53 missense mutations may have gained new oncogenic
functions (GOF), in addition to the loss of classic p53 functions, we will determine if these p53 GOF mutations
affects the sensitivity to Skp2 inhibition. 2) To determine effects of Skp2 inactivation using genetic and
pharmacologic approaches. Four different small molecule Skp2 inhibitors, with distinct molecular targets, will
be used in several novel in vitro and in vivo models. Particular focus will be on SCLC liver metastasis, and on
comparisons between chemotherapy-naïve and chemo-resistant SCLC cells. 3) To determine the antitumor
effects of Skp2 inhibitors in a more clinically relevant mouse tumor model using a large panel of SCLC PDXs
(patient-derived xenografts). Comparisons will be made between PDXs derived from chemotherapy-naïve and
chemo-resistant SCLC tumors, including “isogenic” PDXs derived from serial specimens from the same patient
pre- and post-chemotherapy. When completed, research in this proposal will potentially benefit most SCLC
patients since bi-allelic inactivation of RB1 and TP53 is nearly uniform in SCLC.
Status | Finished |
---|---|
Effective start/end date | 4/12/19 → 3/31/24 |
Funding
- National Cancer Institute: $455,018.00
- National Cancer Institute: $455,018.00
- National Cancer Institute: $455,018.00
- National Cancer Institute: $445,917.00
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.