US-12622906-B2 - Treatment and prognosis of pancreatic cancer

US12622906B2US 12622906 B2US12622906 B2US 12622906B2US-12622906-B2

Abstract

The invention provides a CCR1 antagonist, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of pancreatic cancer, in particular a CCR1 antagonist, for example in combination with one or more further therapeutic agents effective as anti-tumour agents in the treatment of pancreatic cancer. Such an anti-tumour agent may be a chemotherapeutic agent selected from Gemcitabine, Fluorouracil (5-FU), Capecitabine, FOLFIRINOX (Leucovorin Calcium, Fluorouracil, Irinotecan Hydrochloride and Oxaliplatin), Nab-paclitaxel (Abraxane®) and combinations thereof. An immuno-oncology agent (e.g. a PD-1 inhibitor and/or a PD-L1 inhibitor) may also favourably be used with the CCR1 antagonist.

Inventors

Tony James Wu
Michael Gill
Martin Miller
Oliver Cast

Assignees

CAMBRIDGE ENTERPRISE LIMITED

Dates

Publication Date: 20260512
Application Date: 20201218
Priority Date: 20191218

Claims (7)

1 . A method of treating pancreatic cancer in a subject in need of such treatment, said method comprising administering to said subject a therapeutically effective amount of a CCR1 antagonist, or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein the CCR1 antagonist or pharmaceutically acceptable salt, solvate or hydrate thereof is administered to the subject in combination with one or more further therapeutic agents effective as anti-tumour agents in the treatment of pancreatic cancer; and wherein the CCR1 antagonist or pharmaceutically acceptable salt, solvate or hydrate thereof is administered to the subject in combination with a chemotherapeutic agent selected from Gemcitabine, Fluorouracil (5-FU), Capecitabine, FOLFIRINOX (Leucovorin Calcium, Fluorouracil, Irinotecan Hydrochloride and Oxaliplatin), Nab-paclitaxel (Abraxane®) and combinations thereof.
2 . The method according to claim 1 , wherein the CCR1 antagonist or pharmaceutically acceptable salt, solvate or hydrate thereof is administered to the subject in combination with an immuno-oncology agent (e.g. a PD-1 inhibitor and/or a PD-L1 inhibitor).
3 . The method according to claim 1 , wherein the CCR1 antagonist or pharmaceutically acceptable salt, solvate or hydrate thereof is administered to the subject in combination with an MEK inhibitor and/or an IGF1R inhibitor.
4 . The method according to claim 1 , wherein the CCR1 antagonist is selected from UCB-35625, BX-471, AZD-4818, J113863, BAY-865047, BMS-817399, C-4462, CCX-354, CP-481715, and MLN-3897, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
5 . The method according to claim 4 , wherein the CCR1 antagonist is BX-471 and it is administered to the subject in combination with Gemcitabine and optionally a PD-1 inhibitor.
6 . The method according to claim 1 , wherein the pancreatic cancer is a stage III or IV cancer and/or wherein the pancreatic cancer is a Pancreatic ductal adenocarcinoma (PDAC).
7 . The method according to claim 4 , wherein the CCR antagonist is BX-471.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is the National Stage entry under 35 U.S.C. § 371 of International Application No. PCT/GB2020/053295, filed on Dec. 18, 2020, published on Jun. 24, 2021 under Publication Number WO 2021/123813 A8, the entirety of which is herein incorporated by reference. INTRODUCTION The present invention relates to the use of CCR1 antagonists in the treatment of pancreatic cancer. The present invention also relates to the use of pharmaceutical compositions comprising CCR1 antagonists, and to use of CCR1 antagonists in combination with one or more other therapeutic agents for the treatment of pancreatic cancer. Novel methods of treatment and prognosis for pancreatic cancer are also described. BACKGROUND OF THE INVENTION Pancreatic cancer is an aggressive form of cancer which displays very few symptoms until the cancer is in an advanced state. As the name suggests, pancreatic cancer is a disease in which malignant (cancerous) cells form in the tissue of the pancreas. Pancreatic cancer currently represents the tenth most common form of cancer diagnosed in the UK, with 9,912 cases of pancreatic cancer diagnosed in the UK in 2015. Survival rates for patients diagnosed with pancreatic cancer are strikingly low, with is less than 1% of patients diagnosed with pancreatic cancer surviving for more than 10 years. In 2016 alone, 9,263 people in the UK died from pancreatic cancer, a number which roughly correlates to the number of people diagnosed with pancreatic cancer in the UK in the same year. While significant improvements in prevention, detection and treatment over the last 40 years have revolutionised the survival rates of patients diagnosed with most other forms of cancer, clinical outcome for patients diagnosed with pancreatic cancer have remained unyieldingly poor. Pancreatic ductal adenocarcinoma (PDAC), which constitutes over 90% of all pancreatic cancer cases, sees roughly 140,000 new cases globally, making it the fourth-leading cause of cancer-related deaths in the world. The poor clinical outcomes and low survival rates associated with pancreatic cancer are, in part, due to the lack of effective treatment options that are currently available for treating the disease. For instance, the current first-line options for unresectable pancreatic cancer, gemcitabine (Gemzar®) plus nab-paclitaxel (Abraxane®)) and/or FOLFIRINOX (a combination of fluorouracil, leucovorin, irinotecan and oxaliplatin), are chemotherapeutic agents which, if administered to an individual diagnosed with unresectable pancreatic cancer, will on average only extend the life of the individual by 11 months. There, therefore, remains a need for new and improved treatments regimens for pancreatic cancer. Also desired are new methods for prognosing and stratifying patients who have been diagnosed with the disease, such that medical practitioners can make more informed decisions on how best to treat patients with advanced forms of pancreatic cancer. SUMMARY OF THE INVENTION According to a first aspect of the present invention, there is provided a CCR1 antagonist, a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in the treatment of pancreatic cancer. The present inventors determined there to be a strong correlation between CCR1 expressed in pancreatic cancer cells (e.g. PDAC cells) and patient prognosis; the inventors found that high levels of CCR1 correlated strongly to patients with the worst clinical outcomes. The inventors further found that high levels of immune (e.g. macrophage) infiltration also correlated well with poor patient prognosis. The inventors were therefore able to identify new biomarkers and methods for prognosing pancreatic cancer patients. Furthermore, the inventors found that a number of structurally distinct CCR1 antagonists were effective at both disrupting macrophage-mediated pro-invasive characteristics of pancreatic cancer cells, and reducing CCR1 expression levels. In vivo tumour growth studies confirmed that the administration of a CCR1 antagonist (e.g. BX-471) resulted in a significant inhibition to the growth of pancreatic cancer cells (e.g. PDAC cells), particularly when the pancreatic cancer cells were also exposed to macrophages. The inventors have also found that inclusion of a CCR1 antagonist with standard of care drug treatment increased the survival time of mice in a murine model of pancreatic ductal adenocarcinoma (PDAC). A CCR1 antagonist for use according to the invention is especially effective in the treatment of pancreatic cancer when it is used in combination with an established treatment regimen, such as a treatment often referred to as ‘standard of care’. Such combinations are discussed in further detail below. In a preferred embodiment, there is provided a CCR1 antagonist, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in the treatment of pancreatic cancer in combination with one or more chemotherapeutic age