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← Swipe left and right to view, click [Read the original text] to learn more → Triple Negative Breast Cancer (TNBC) is a very aggressive and heterogeneous basal-like tumor, accounting for 15-20% of breast cancer cases, three classics Targets: estrogen receptor (ER), progesterone receptor (progesterone receptor) and human epidermal growth factor receptor 2 (HER2) lack expression
.
Therefore, the choice of targets for the development of triple-negative breast cancer drugs has become the key
.
Eight triple-negative breast cancer drug targets, TNBC patients, did not respond to traditional ER and HER2 targeted therapies
.
Therefore, combined treatment of surgical resection, radiotherapy and systemic chemotherapy is still the main treatment for this patient group
.
The clinical benefits of these treatment options are limited, and adverse events such as cardiotoxicity and neutropenia are common
.
Even after treatment, primary TNBC tumors often metastasize to distant organs, including lungs and brain, which is the reason for the low survival rate of TNBC patients
.
Searching for specific targets and developing new pharmaceutical preparations will become the future of triple-negative breast cancer treatment
.
Drug targets for triple-negative breast cancer (Reference 3) 1.
10% of TNBC patients with PARP have BRCA1/2 copy number deletion or loss-of-function mutations
.
The PARP enzyme family uses NAD+DNA damage sensors, which are most active in the S phase of the cell cycle and play a key role in DNA repair
.
Small molecule NAD+ mimics such as olaparib, talazoparib, niraparib, rucaparib, and veleparib inhibit the catalytic activity of PARP and act through "synthetic lethality".
Olaparib (olaparib, Lynparza) and Talazoparib have been approved by the FDA for treatment Breast cancer susceptibility gene 1/2 (BRCA1/2) germline mutations in HER2-negative advanced breast cancer
.
The progression-free survival (PFS) of TNBC patients who received olaparib chemotherapy was 7 months, while patients who received single-agent chemotherapy showed a PFS of 4.
2 months (NCT02000622)
.
Other drugs are currently in the late stage of clinical trials as single drugs or combination treatments
.
2.
The PD-L1/PD-1 FDA approved the anti-PD-L1 monoclonal antibody atezolizumab combined with the chemotherapy drug nab-paclitaxel for the treatment of PD-L1-positive unresectable, locally advanced or metastatic TNBC.
Among TNBC patients receiving this therapy The overall survival period has been extended by nearly 10 months
.
The FDA approved the ventana PD-L1 (SP142) test as a companion diagnosis of atezolizumab
.
In 2020, the FDA also approved pembrolizumab combined with chemotherapy for locally recurrent unresectable or metastatic TNBC patients whose tumors express PD-L1 (CPS≥10)
.
Dako's IHC 22C3 pharmDx is used as a companion diagnosis
.
The median PFS was 9.
7 months and the placebo group was 5.
6 months
.
3.
Trop2Trop-2 is overexpressed in many solid tumors, but its expression is limited in normal tissues
.
Trop-2 plays a role in tumorigenesis and is associated with the poor prognosis of several cancers including breast cancer
.
On April 22, 2020, the first Trop2-ADC drug sacituzumab govitecan was approved to treat metastatic TNBC
.
Phase 1/2 IMMU-132-01 (NCT01631552) study: 108 patients with metastatic TNBC, the primary endpoint ORR was 33.
3% (95%CI 24.
6-43.
1), 3 CRs and 33 PRs, median duration of response (DOR) was 7.
7 months (95% confidence interval 4.
9-10.
8), median progression-free survival (PFS) was 5.
5 months (95% CI4.
1-6.
3), median overall survival (OS) was 13.
0 months (95%CI 11.
2-13.
7)
.
The multicenter, randomized, phase III ASCENT trial (NCT02574455) was stopped earlier than planned due to convincing evidence
.
4.
EGFR epidermal growth factor receptor (EGFR) is highly expressed in 50% of TNBC patients and is related to the poor prognosis of TNBC patients.
However, targeted anti-EGFR therapy has shown limited efficacy of TNBC therapy in both clinical and preclinical studies
.
Therefore, combination with other therapeutic drugs such as PRAP inhibitors, or the development of bispecific antibodies, such as EGFRXHER3 double antibodies, has become an option
.
EGFRXHER3 double anti-HER3 is another target with high expression in triple-negative breast cancer, but its own tyrosine kinase activity is low, and the effect of small molecule inhibitors is not good
.
Therefore, some researchers construct bispecific antibodies based on EGFR antibody (cetuximab (IgG hu225)) and HER3 antibody (IgG 3-43), which can down-regulate p-EGFR (Y1068) and p-HER3 (Y1289) in mechanism, and Downstream effects p-AKT (T308) and p-ERK (T202/Y204), and can reduce TNBC cancer stem cells ((ALDHHigh) in mouse models
.
In the previous EGFRXHER3 double antibody clinical trials (NCT01577173, NCT01652482), it was confirmed The safety of this type of double antibody can increase the sensitivity of TNBC to PI3K inhibitors, which provides a basis for the development of combination therapy
.
EGFRXHER3 double antibody (Document 2) 5.
Notch evolutionary conservative Notch signal and cancer biology Many aspects have important relevance, especially cancer stem cells
.
Five typical Notch ligands (DLL1, DLL3, DLL4, Jagged1 and Jagged2) and four Notch receptor analogs (Notch1, 2,3,4), reflecting the complexity of its versatility and functional activity
.
as shown below, Notch involved in tumor growth, invasion and metastasis, chemotherapy resistant cancer stem cell differentiation
.
of Notch signaling pathway with TNBC (literature 4) EGFR×Notch double antibody EGFR×Notch double antibody has also been confirmed to act on the PI3K signaling pathway, down-regulating p-EGFR (Y1068) and p-HER3 (Y1289), as well as downstream effects p-AKT (T308) and p-ERK (T202 / Y204), reducing the population of cancer stem cells (Document.
5)
.
6.
AKT in TNBC PI3K-AKT signaling pathway very active, and thus TNBC AKT inhibitor has become the focus of drug development
.
Ipataserib (GDC-0068) (Genentech) NCT02162719, A Study Assessing the Safety and Efficacy of Adding Ipatasertib to Paclitaxel Treatment in Participants With Breast Cancer That Has Spread Beyond the Initial Site, and the Cancer Does Not Have Certain Hormonal Receptors (LOTUS), Phase2 2020 ESMO breast cancer special meeting, in patients with normal IHC PTEN expression, the median OS of Ipataserib and placebo groups were 28.
5 months and 17.
1 months (HR: 0.
70); the 1-year OS rate was 85% and 68%
.
Among patients with low PTEN expression, the median OS was 23.
1 months and 15.
8 months (HR: 0.
83) and the 1-year OS rate was 79% and 64%
.
Capivasertib (AZD5363) (AstraZeneca) NCT02423603, PAKT: AZD5363 in Combination With Paclitaxel in Triple-Negative Advanced or Metastatic Breast Cancer (PAKT), Phase2 Compared with the placebo plus paclitaxel group, the median PFS of Capivasertib plus paclitaxel improved ( 5.
9 months vs.
4.
2 months; HR: 0.
74)
.
The median OS of Capivasertib plus paclitaxel was 19.
1 months, and the median OS of placebo plus paclitaxel was 12.
6 months (HR: 0.
61)
.
More importantly, in patients with tumors with PIK3CA/AKT1/PTEN changes, the median PFS of Capivasertib plus paclitaxel was 9.
3 months, and that of placebo plus paclitaxel was 3.
7 months (HR: 0.
30)
.
7.
The LAR subtype of the androgen receptor TNBC is characterized by the expression of androgen receptor (AR) and its downstream effectors
.
Anti-androgen receptor therapy has certain clinical benefits
.
For example, the clinical study conducted by AstraZeneca and Memorial Sloan Kettering Cancer Center (NCT00468715), using bicalutamide treatment, the 6-month CBR (clinical benefit rate) was 19%, and the PFS was 12 weeks
.
8.
ROR1ROR1 is expressed on the surface of many solid tumors (including TNBC)
.
NBE-002, developed by NBE-Therapeutics AG, is an ADC drug that is site-coupled from a humanized monoclonal antibody against the receptor tyrosine kinase ROR1 and a derivative of the high-efficiency anthracycline PNU-159682
.
It has the best anti-tumor activity against TNBC in the PDX model
.
A clinical study is currently registered (NCT04441099, NBE-002 in Patients With Advanced Solid Tumors, Phase 1/2)
.
The editor concludes that breast cancer is the number one cancer in women, and triple-negative breast cancer accounts for 15-20%
.
Because classic targets such as ER, progesterone, and HER2 are not expressed, it is necessary to find other targets for drug development
.
The editor summarizes eight popular targets, including PARP, AKT, Notch, PD-1/PD-L1, ROR1, Trop2, AR, EGFR, etc.
Among them, PD-1/PD-L1, PARP and Trop2 have been drug-obtained While AKT inhibitors have entered phase 2 clinical trials, other targets are also in different stages of clinical trials, laying the foundation for the future capture of triple-negative breast cancer
.
References 1.
Sundee Dees et al, Bispecific Antibodies for Triple Negative Breast Cancer, Trends Cancer.
2021 Feb;7(2):162-173.
2.
Sukumar, Jasmine; Gast, Kelly; Quiroga, Dionisia; Lustberg, Maryam; Williams, Nicole (2020).
Triple-negative breast cancer: promising prognostic biomarkers currently in development.
Expert Review of Anticancer Therapy.
3.
Rau, A.
; Lieb, WS; Seifert, O.
; Honer, J.
; Birnstock, D.
; Richter, F.
; Aschmoneit, N.
; Olayioye, MA; Kontermann, RE Inhibition of Tumor Cell Growth and Cancer Stem Cell Expansion by a Bispecific Antibody Targeting EGFR and HER3.
Mol.
Cancer 2020, 19, 1474–1485.
4.
Giuli MV, Giuliani E, Screpanti I, Bellavia D, Checquolo S.
Notch Signaling Activation as a Hallmark for Triple-Negative Breast Cancer Subtype.
J Oncol, 2019, 8707053 (2019) 5.
Fu, W.
et al.
(2019) EGFR/Notch antagonists enhance the response to inhibitors of the PI3K-Akt pathway by decreasing tumor-initiating cell frequency.
Clin.
Cancer Res.
25, 2835-2846.
Abstract LB-197: NBE-002, an anthracycline-based immune-stimulatory antibody drug conjugate (iADC) targeting ROR1 for the treatment of triple-negative breast cancer, DOI: 10.
1158/1538-7445.
▼Click [Read the original text] to learn more~
.
Therefore, the choice of targets for the development of triple-negative breast cancer drugs has become the key
.
Eight triple-negative breast cancer drug targets, TNBC patients, did not respond to traditional ER and HER2 targeted therapies
.
Therefore, combined treatment of surgical resection, radiotherapy and systemic chemotherapy is still the main treatment for this patient group
.
The clinical benefits of these treatment options are limited, and adverse events such as cardiotoxicity and neutropenia are common
.
Even after treatment, primary TNBC tumors often metastasize to distant organs, including lungs and brain, which is the reason for the low survival rate of TNBC patients
.
Searching for specific targets and developing new pharmaceutical preparations will become the future of triple-negative breast cancer treatment
.
Drug targets for triple-negative breast cancer (Reference 3) 1.
10% of TNBC patients with PARP have BRCA1/2 copy number deletion or loss-of-function mutations
.
The PARP enzyme family uses NAD+DNA damage sensors, which are most active in the S phase of the cell cycle and play a key role in DNA repair
.
Small molecule NAD+ mimics such as olaparib, talazoparib, niraparib, rucaparib, and veleparib inhibit the catalytic activity of PARP and act through "synthetic lethality".
Olaparib (olaparib, Lynparza) and Talazoparib have been approved by the FDA for treatment Breast cancer susceptibility gene 1/2 (BRCA1/2) germline mutations in HER2-negative advanced breast cancer
.
The progression-free survival (PFS) of TNBC patients who received olaparib chemotherapy was 7 months, while patients who received single-agent chemotherapy showed a PFS of 4.
2 months (NCT02000622)
.
Other drugs are currently in the late stage of clinical trials as single drugs or combination treatments
.
2.
The PD-L1/PD-1 FDA approved the anti-PD-L1 monoclonal antibody atezolizumab combined with the chemotherapy drug nab-paclitaxel for the treatment of PD-L1-positive unresectable, locally advanced or metastatic TNBC.
Among TNBC patients receiving this therapy The overall survival period has been extended by nearly 10 months
.
The FDA approved the ventana PD-L1 (SP142) test as a companion diagnosis of atezolizumab
.
In 2020, the FDA also approved pembrolizumab combined with chemotherapy for locally recurrent unresectable or metastatic TNBC patients whose tumors express PD-L1 (CPS≥10)
.
Dako's IHC 22C3 pharmDx is used as a companion diagnosis
.
The median PFS was 9.
7 months and the placebo group was 5.
6 months
.
3.
Trop2Trop-2 is overexpressed in many solid tumors, but its expression is limited in normal tissues
.
Trop-2 plays a role in tumorigenesis and is associated with the poor prognosis of several cancers including breast cancer
.
On April 22, 2020, the first Trop2-ADC drug sacituzumab govitecan was approved to treat metastatic TNBC
.
Phase 1/2 IMMU-132-01 (NCT01631552) study: 108 patients with metastatic TNBC, the primary endpoint ORR was 33.
3% (95%CI 24.
6-43.
1), 3 CRs and 33 PRs, median duration of response (DOR) was 7.
7 months (95% confidence interval 4.
9-10.
8), median progression-free survival (PFS) was 5.
5 months (95% CI4.
1-6.
3), median overall survival (OS) was 13.
0 months (95%CI 11.
2-13.
7)
.
The multicenter, randomized, phase III ASCENT trial (NCT02574455) was stopped earlier than planned due to convincing evidence
.
4.
EGFR epidermal growth factor receptor (EGFR) is highly expressed in 50% of TNBC patients and is related to the poor prognosis of TNBC patients.
However, targeted anti-EGFR therapy has shown limited efficacy of TNBC therapy in both clinical and preclinical studies
.
Therefore, combination with other therapeutic drugs such as PRAP inhibitors, or the development of bispecific antibodies, such as EGFRXHER3 double antibodies, has become an option
.
EGFRXHER3 double anti-HER3 is another target with high expression in triple-negative breast cancer, but its own tyrosine kinase activity is low, and the effect of small molecule inhibitors is not good
.
Therefore, some researchers construct bispecific antibodies based on EGFR antibody (cetuximab (IgG hu225)) and HER3 antibody (IgG 3-43), which can down-regulate p-EGFR (Y1068) and p-HER3 (Y1289) in mechanism, and Downstream effects p-AKT (T308) and p-ERK (T202/Y204), and can reduce TNBC cancer stem cells ((ALDHHigh) in mouse models
.
In the previous EGFRXHER3 double antibody clinical trials (NCT01577173, NCT01652482), it was confirmed The safety of this type of double antibody can increase the sensitivity of TNBC to PI3K inhibitors, which provides a basis for the development of combination therapy
.
EGFRXHER3 double antibody (Document 2) 5.
Notch evolutionary conservative Notch signal and cancer biology Many aspects have important relevance, especially cancer stem cells
.
Five typical Notch ligands (DLL1, DLL3, DLL4, Jagged1 and Jagged2) and four Notch receptor analogs (Notch1, 2,3,4), reflecting the complexity of its versatility and functional activity
.
as shown below, Notch involved in tumor growth, invasion and metastasis, chemotherapy resistant cancer stem cell differentiation
.
of Notch signaling pathway with TNBC (literature 4) EGFR×Notch double antibody EGFR×Notch double antibody has also been confirmed to act on the PI3K signaling pathway, down-regulating p-EGFR (Y1068) and p-HER3 (Y1289), as well as downstream effects p-AKT (T308) and p-ERK (T202 / Y204), reducing the population of cancer stem cells (Document.
5)
.
6.
AKT in TNBC PI3K-AKT signaling pathway very active, and thus TNBC AKT inhibitor has become the focus of drug development
.
Ipataserib (GDC-0068) (Genentech) NCT02162719, A Study Assessing the Safety and Efficacy of Adding Ipatasertib to Paclitaxel Treatment in Participants With Breast Cancer That Has Spread Beyond the Initial Site, and the Cancer Does Not Have Certain Hormonal Receptors (LOTUS), Phase2 2020 ESMO breast cancer special meeting, in patients with normal IHC PTEN expression, the median OS of Ipataserib and placebo groups were 28.
5 months and 17.
1 months (HR: 0.
70); the 1-year OS rate was 85% and 68%
.
Among patients with low PTEN expression, the median OS was 23.
1 months and 15.
8 months (HR: 0.
83) and the 1-year OS rate was 79% and 64%
.
Capivasertib (AZD5363) (AstraZeneca) NCT02423603, PAKT: AZD5363 in Combination With Paclitaxel in Triple-Negative Advanced or Metastatic Breast Cancer (PAKT), Phase2 Compared with the placebo plus paclitaxel group, the median PFS of Capivasertib plus paclitaxel improved ( 5.
9 months vs.
4.
2 months; HR: 0.
74)
.
The median OS of Capivasertib plus paclitaxel was 19.
1 months, and the median OS of placebo plus paclitaxel was 12.
6 months (HR: 0.
61)
.
More importantly, in patients with tumors with PIK3CA/AKT1/PTEN changes, the median PFS of Capivasertib plus paclitaxel was 9.
3 months, and that of placebo plus paclitaxel was 3.
7 months (HR: 0.
30)
.
7.
The LAR subtype of the androgen receptor TNBC is characterized by the expression of androgen receptor (AR) and its downstream effectors
.
Anti-androgen receptor therapy has certain clinical benefits
.
For example, the clinical study conducted by AstraZeneca and Memorial Sloan Kettering Cancer Center (NCT00468715), using bicalutamide treatment, the 6-month CBR (clinical benefit rate) was 19%, and the PFS was 12 weeks
.
8.
ROR1ROR1 is expressed on the surface of many solid tumors (including TNBC)
.
NBE-002, developed by NBE-Therapeutics AG, is an ADC drug that is site-coupled from a humanized monoclonal antibody against the receptor tyrosine kinase ROR1 and a derivative of the high-efficiency anthracycline PNU-159682
.
It has the best anti-tumor activity against TNBC in the PDX model
.
A clinical study is currently registered (NCT04441099, NBE-002 in Patients With Advanced Solid Tumors, Phase 1/2)
.
The editor concludes that breast cancer is the number one cancer in women, and triple-negative breast cancer accounts for 15-20%
.
Because classic targets such as ER, progesterone, and HER2 are not expressed, it is necessary to find other targets for drug development
.
The editor summarizes eight popular targets, including PARP, AKT, Notch, PD-1/PD-L1, ROR1, Trop2, AR, EGFR, etc.
Among them, PD-1/PD-L1, PARP and Trop2 have been drug-obtained While AKT inhibitors have entered phase 2 clinical trials, other targets are also in different stages of clinical trials, laying the foundation for the future capture of triple-negative breast cancer
.
References 1.
Sundee Dees et al, Bispecific Antibodies for Triple Negative Breast Cancer, Trends Cancer.
2021 Feb;7(2):162-173.
2.
Sukumar, Jasmine; Gast, Kelly; Quiroga, Dionisia; Lustberg, Maryam; Williams, Nicole (2020).
Triple-negative breast cancer: promising prognostic biomarkers currently in development.
Expert Review of Anticancer Therapy.
3.
Rau, A.
; Lieb, WS; Seifert, O.
; Honer, J.
; Birnstock, D.
; Richter, F.
; Aschmoneit, N.
; Olayioye, MA; Kontermann, RE Inhibition of Tumor Cell Growth and Cancer Stem Cell Expansion by a Bispecific Antibody Targeting EGFR and HER3.
Mol.
Cancer 2020, 19, 1474–1485.
4.
Giuli MV, Giuliani E, Screpanti I, Bellavia D, Checquolo S.
Notch Signaling Activation as a Hallmark for Triple-Negative Breast Cancer Subtype.
J Oncol, 2019, 8707053 (2019) 5.
Fu, W.
et al.
(2019) EGFR/Notch antagonists enhance the response to inhibitors of the PI3K-Akt pathway by decreasing tumor-initiating cell frequency.
Clin.
Cancer Res.
25, 2835-2846.
Abstract LB-197: NBE-002, an anthracycline-based immune-stimulatory antibody drug conjugate (iADC) targeting ROR1 for the treatment of triple-negative breast cancer, DOI: 10.
1158/1538-7445.
▼Click [Read the original text] to learn more~
